JP2022544776A - Compounds and compositions for differential modulation of nicotinamide adenine dinucleotide - Google Patents

Abstract

The present invention relates to compounds and compositions for differential modulation of nicotinamide adenine dinucleotide (NAD) in various tissues or cell types. Furthermore, the present invention relates to pharmaceutical compositions comprising one or more NAD modulating compounds as active pharmaceutical ingredients. The invention also relates to methods of making such compounds and compositions. Methods of using such compounds or compositions include administering such compounds and compositions to promote the increase or maintenance of intracellular levels of nicotinamide adenine dinucleotide (NAD) in healthy cells and tissues, thus promoting healthy cells and tissues. Including improving cell and tissue survival. Also included are methods of increasing or maintaining intracellular levels of NAD in selected cells or tissues while simultaneously reducing NAD levels in unhealthy tissues or cells, thus reducing survival of unhealthy cells and tissues. [Selection figure] None

Description

This application claims priority to U.S. Provisional Patent Application No. 62/886,869, filed August 14, 2019, and U.S. Provisional Patent Application No. 62/889,376, filed August 20, 2019. , each of which is incorporated herein by reference in its entirety.

Nicotinamide adenine dinucleotide (NAD) and related naturally occurring compounds are known as essential coenzymes for cellular redox reactions in all living organisms. Several lines of evidence suggest that NAD is involved in poly(ADP-ribosyl)ylation in DNA repair (Menissier de Murcia et al., EMBO J., (2003) 22, 2255-2263), immune response and G protein-coupled signaling. (Corda et al., EMBO J., (2003) 22, 1953-8) and the synthesis of cyclic ADP-ribose and nicotinate adenine dinucleotide phosphate (NAADP) in intracellular calcium signaling. It has been shown to be involved in a number of important signaling pathways in mammalian cells, including (Lee, Annu. Rev. Pharmacol. Toxicol., (2001) 41, 317-345). NAD and its metabolites have also been shown to play important roles in transcriptional regulation (Lin et al., Curr. Opin. Cell. Biol., (2003) 15, 241-246). In particular, the discovery of Sir2 NAD-dependent deacetylase activity has been reported (eg, Imai et al., Nature, (2000) 403, 795-800; Landry et al., Biochem. Biophys. Res. Commun., (2000) 278, 685-690; Smith USA, (2000) 97, 6658-6663) focused attention on this role of NAD. Nicotinamide phosphoribosyltransferase (NAMPT) plays a role in the salvage pathway of NAD+ synthesis and the compound FK866 is a small molecule inhibitor of NAMPT (Kang et al., Mol. Cells, 27, 667-671, 2009; Galli et al. , J. Med. Chem. 2013, 56, 16, 6279-6296). Various other NAMPT inhibitors have been reported (eg Industry-Academic Cooperation Foundation, Yonsei University, EP3 431 472 A2).

Despite advances in understanding the biology of NAD, pharmacological intervention and/or controlled modulation of the NAD pathway in living cells and tissues, including modulation of the NAD pathway that is not possible with naturally occurring compounds, remains a challenge. There remains a need for improved compositions for and methods of using such compositions.

The present invention relates to compounds and compositions for the modulation of nicotinamide adenine dinucleotide (NAD, also called NAD+ in its oxidized form and NADH in its reduced form). In some embodiments, this invention relates to methods of making such compounds and compositions. In some embodiments, the present invention relates to pharmaceutical compositions containing one or more NAD modulating compounds as a single active pharmaceutical ingredient or in combination with one or more other active pharmaceutical ingredients. In further embodiments, the present invention uses such compounds or compositions to promote intracellular delivery of nicotinamide adenine dinucleotide (NAD) in cells and tissues to treat disease and/or improve cell and tissue survival. It relates to a method of promoting an increase in level. Methods of using such compounds or compositions include administering such compounds and compositions to promote the increase or maintenance of intracellular levels of nicotinamide adenine dinucleotide (NAD) in healthy cells and tissues, thus promoting healthy cells and tissues. Including improving or protecting cell and tissue survival. Also included are methods of increasing or maintaining intracellular levels of NAD in selected cells or tissues while simultaneously reducing NAD levels in unhealthy tissues or cells, thus reducing the viability of unhealthy cells and tissues. . In certain embodiments, the present invention uses such compounds or compositions to enhance the viability of unhealthy cells and tissues by differentially reducing intracellular levels of NAD. to a greater than any reduction in .

FIG. 4 shows NAD(H) in cells after treatment with control or compound according to Formula 1. FIG. FIG. 4 shows NAD(H) in cells after treatment with control or compound according to Formula 1. FIG. FIG. 4 shows NAD(H) in normal cells after treatment with control or compound according to Formula 1. FIG. FIG. 4 shows NAD(H) in normal cells after treatment with control or compound according to Formula 1. FIG. FIG. 4 shows NAD(H) in normal cells after treatment with control or compound according to Formula 1. FIG. FIG. 2 shows NAD(H) in cancer cells after treatment with control or compound according to Formula 1. FIG. FIG. 2 shows NAD(H) in cancer cells after treatment with control or compound according to Formula 1. FIG. FIG. 2 shows NAD(H) in cancer cells after treatment with control or compound according to Formula 1. FIG. FIG. 2 shows NAD(H) in cancer cells after treatment with control or compound according to Formula 1. FIG. FIG. 3 shows NAD(H) levels and viability in normal cells (Hek293 cells/human embryonic kidney cells) after treatment with control or compounds according to Formula 1 as an indicator of cytotoxicity/cytostatics. FIG. 3 shows NAD(H) levels and viability in normal cells (Hek293 cells/human embryonic kidney cells) after treatment with control or compounds according to Formula 1 as an indicator of cytotoxicity/cytostatics. FIG. 4 shows NAD(H) levels and viability in cancer cells (HepG2 cells/human hepatocellular carcinoma) after treatment with control or compounds according to Formula 1 as an indicator of cytotoxicity/cytostatics. FIG. 4 shows NAD(H) levels and viability in cancer cells (HepG2 cells/human hepatocellular carcinoma) after treatment with control or compounds according to Formula 1 as an indicator of cytotoxicity/cytostatics. FIG. 4 shows NAD(H) in cells after treatment with control or compound according to Formula 1. FIG. FIG. 4 shows NAD(H) in cells after treatment with control or compound according to Formula 1. FIG.

DEFINITIONS Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art in this disclosure. As used herein, the following terms have the meaning ascribed to them unless otherwise specified.

In this disclosure, the terms "comprise," "include," "contain," and "having," etc., may have the meaning ascribed to them in US patent law, and include, "include," "include," etc. and "consisting essentially of" or "consisting essentially of" similarly has the meaning ascribed to the term in U.S. Patent Law, which term is open-ended and enumerated Allows for the presence of others than those recited, but excludes prior art embodiments, so long as the basic or novel features of the subject matter are not altered by the presence of others.

Ranges provided herein are understood to be shorthand for all of the values within the range. For example, the range 1 to 50 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49 or 50.

The phrase "a" or "an" entity, as used herein, refers to one or more of that entity, e.g., a compound refers to one or more compounds or It refers to at least one chemical compound. As such, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein.

Unless specifically stated otherwise or clear from the context, the term "about," as used herein, means within the usual tolerances in the art, e.g., within 2 standard deviations of the mean. is understood. About is within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value can be understood as All numerical values provided herein are modified by the term about, unless the context clearly dictates otherwise.

The term "acyl" is art-recognized and refers to a group of the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group, and can be represented, for example, by the formula hydrocarbyl C(O)NH-.

The term "acyloxy" is art-recognized and refers to a group of the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

The term "alkoxy" refers to an oxygen-bonded alkyl group, preferably a lower alkyl group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, and can be represented by the general formula alkyl-O-alkyl.

The term "alkenyl," as used herein, refers to an aliphatic group containing at least one double bond, and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," The latter of which refers to alkenyl moieties having substituents replacing hydrogens on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Further, such substituents include all contemplated for alkyl groups, as described below, except where stability prohibits their use. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

An "alkyl" group or "alkane" is a fully saturated, straight chain or branched non-aromatic hydrocarbon. Typically, a straight or branched chain alkyl group has 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms, unless otherwise defined. Examples of straight chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C ₁ -C ₆ straight or branched alkyl group is also referred to as a “lower alkyl” group.

Furthermore, the term "alkyl" (or "lower alkyl") when used throughout the specification, examples and claims includes both "unsubstituted alkyl" and "substituted alkyl". is intended, the latter of which refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, include, for example, halogen, hydroxyl, carbonyl (e.g. carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g. thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, Phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moieties. It will be appreciated by those skilled in the art that moieties substituted on the hydrocarbon chain may themselves be substituted when appropriate. For example, substituted and unsubstituted alkyl substituents include amino, azide, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyls and sulfonates), and Silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates and esters), _-CF3 , -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, _-CF3 , -CN, and the like.

The term "C _xy " when used with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy is meant to include groups containing x to y carbons in the chain. means. For example, the term "C _xy alkyl" refers to straight chain alkyl containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, and Refers to a substituted or unsubstituted saturated hydrocarbon group, including branched chain alkyl groups. C ₀ alkyl denotes a hydrogen when the group is in the terminal position and a bond when it is internal. The terms "C2 _-y alkenyl" and "C2 _-y alkynyl" are analogous in length and possible substitution to the alkyls described above, but contain at least one double or triple bond, respectively. or refers to an unsubstituted unsaturated aliphatic group.

The term "alkylamino," as used herein, refers to amino groups substituted with at least one alkyl group.

The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group, and can be represented by the general formula alkylS-.

The term "alkynyl," as used herein, refers to an aliphatic group containing at least one triple bond, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," in which The latter of refers to alkynyl moieties having substituents replacing hydrogens on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Further, such substituents include all contemplated for alkyl groups, as described above, except where stability prohibits their use. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term "amide," as used herein, refers to

を指し、式中、各R³⁰は独立して水素若しくはヒドロカルビル基を表し、又は2つのR³⁰が、結合しているN原子と一緒になって、環構造内に4～8個の原子を有する複素環を完結している。

wherein each R ³⁰ independently represents hydrogen or a hydrocarbyl group, or two R ^30s , together with the N atom to which they are attached, represent 4 to 8 atoms in the ring structure completes the heterocycle with

The terms "amine" and "amino" are art-recognized and include both unsubstituted and substituted amines and salts thereof, e.g.

で表され得る部分を指し、式中、各R³¹は独立して水素若しくはヒドロカルビル基を表し、又は2つのR³¹が、結合しているN原子と一緒になって、環構造内に4～8個の原子を有する複素環を完結している。「アミノアルキル」という用語は、本明細書で使用される場合、アミノ基で置換されたアルキル基を指す。

wherein each R ³¹ independently represents hydrogen or a hydrocarbyl group, or two R ³¹ , together with the N atom to which they are attached, are in the ring structure from 4 to Complete heterocycle with 8 atoms. The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

The term "aryl," as used herein, includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5-7 membered ring, more preferably a 6 membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being aromatic. For example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and/or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term "carbamate" is art-recognized and

を指し、式中R³²及びR³³は独立して、水素又はヒドロカルビル基、例えばアルキル基を表し、又はR³²及びR³³は、介在原子と一緒になって、環構造内に4～8個の原子を有する複素環を完結している。

wherein R ³² and R ³³ independently represent hydrogen or a hydrocarbyl group such as an alkyl group, or R ³² and R ³³ together with intervening atoms are 4 to 8 in the ring structure completes the heterocycle with the atoms

The terms "carbocycle" and "carbocyclic" as used herein refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings that are saturated on all carbon atoms and cycloalkene rings that contain at least one double bond.

The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or more atoms are shared between the two rings. The term "fused carbocycle" refers to bicyclic carbocycles in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In exemplary embodiments, an aromatic ring such as phenyl may be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings is included in the definition of carbocyclic when valences permit. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octa-3 -ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0 ]hept-3-ene. A “carbocycle” may be substituted at any one or more positions capable of bearing a hydrogen atom.

A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyl groups have from 3 to about 10 carbon atoms, more typically from 3 to 8 carbon atoms, unless otherwise defined. The second ring of bicyclic cycloalkyls can be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which 1, 2 or 3 or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to bicyclic cycloalkyls in which each ring shares two adjacent atoms with the other ring. The second ring of the fused bicyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

The term "carbonate" is art-recognized and refers to the group ^-OCO2 _- R34, where ^R34 represents a hydrocarbyl group.

The term "carboxy," as used herein, refers to a group of formula _-CO2H .

The term "ester" as used herein refers to the group -C(O) ^OR35 , where ^R35 represents a hydrocarbyl group.

The term "ether," as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers may be symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups which can be represented by the general formula alkyl-O-alkyl.

The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo and iodo.

The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

The term "heteroalkyl," as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” refer to a substituted or unsubstituted aromatic monocyclic ring structure (preferably 5- to 7-membered ring, more preferably 5- to 6-membered ring), wherein the ring structure contains at least one structures containing 1 heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where the ring at least one of which is heteroaromatic, eg the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and/or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

The term "heteroatom," as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

The terms "heterocyclyl", "heterocycle" and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure (preferably 3- to 10-membered, more preferably 3- to 7-membered) Refers to structures in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, and more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where At least one of the rings is heterocyclic, eg the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and/or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocyclic group.

The term "hydrocarbyl," as used herein, refers to groups bonded through carbon atoms having no =O or =S substituents, typically at least one carbon-hydrogen bond and have a predominantly carbon skeleton, but may optionally contain heteroatoms. Thus, although groups such as methyl, ethoxyethyl, 2-pyridyl and trifluoromethyl are considered hydrocarbyls for the purposes of this application, acetyl (having an =O substituent on the linking carbon) and ethoxy (having an oxygen are not considered hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl and combinations thereof.

The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

The term "lower" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy has no more than 10, preferably no more than 6 non-hydrogen atoms in the substituent. is meant to include groups. A "lower alkyl", for example, refers to an alkyl group containing 10 or fewer, preferably 6 or fewer carbon atoms. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents as defined herein may be used alone or in combination with other substituents, for example in the hydroxyalkyl and aralkyl recitations lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or It is lower alkoxy.

The terms "polycyclyl", "polycyclic" and "polycyclic" refer to two or more rings in which two or more atoms are common to two adjacent rings, e.g. the rings are "fused rings". (eg, cycloalkyl(s), cycloalkenyl(s), cycloalkynyl(s), aryl(s), heteroaryl(s), and/or heterocyclyl(s)). Each ring of the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring of a polycyclic ring contains 3-10, preferably 5-7 atoms in the ring.

The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached.

The term "substituted" refers to moieties that have substituents replacing hydrogens on one or more carbons of the backbone. "Substituted" or "substituted with" indicates that such substitutions are subject to the permissible valences of the atom and substituents being substituted, and that substitutions voluntarily undergo transformations, e.g., by rearrangement, cyclization, elimination, etc. It will be understood to include the implied condition of providing a stable compound that does not undergo chemical reactions. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents may be any substituent described herein, e.g. halogen, hydroxyl, carbonyl (e.g. carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g. thioester, thioacetate or thioformate), alkoxy, phosphoryl, Phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moieties. It will be appreciated by those skilled in the art that substituents may themselves be substituted where appropriate. It is understood that references herein to chemical moieties include substitution variations, unless specifically stated as "unsubstituted." For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variations.

The term "sulfate" is art-recognized and refers to the group _-OSO3H or a pharmaceutically acceptable salt thereof.

The term "sulfonamide" is art-recognized and refers to the general formula

で表される基を指し、式中R³⁶及びR³⁷は独立して、水素又はヒドロカルビル、例えばアルキルを表し、又はR³⁶及びR³⁷は、介在原子と一緒になって、環構造内に4個～8個の原子を有する複素環を完結している。

wherein R ³⁶ and R ³⁷ independently represent hydrogen or hydrocarbyl, such as alkyl, or R ³⁶ and R ³⁷ together with intervening atoms form 4 Complete heterocycles with 1 to 8 atoms.

The term "sulfoxide" is art-recognized and refers to the group -S(O) ^-R38 , where ^R38 represents hydrocarbyl.

The term "sulfonate" is art _- recognized and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

The term "sulfone" is art-recognized and refers to the group -S(O) ₂ - ^R39 , where ^R39 represents hydrocarbyl.

The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

The term "thioester" as used herein refers to the group -C(O) ^SR40 or ^-SC (O)R40, where ^R10 represents hydrocarbyl.

The term "thioether," as used herein, is equivalent to an ether in which the oxygen has been replaced with sulfur.

The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces or prevents the reactivity of that functional group. Typically, protecting groups can be selectively removed as desired during synthesis. Examples of protecting groups are Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Edition, 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vol. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2- Including trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (such as TMS or TIPS groups), glycol ethers such as ethylene glycol and propylene glycol derivatives, and allyl ethers.

In certain embodiments, compounds of the invention may be racemates. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, the compounds of the invention have a or even have an ee of about 95% or greater. In certain embodiments, compounds of the invention may possess more than one stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomers. For example, the compounds of the invention have a or even may have about 95% de or greater.

In certain embodiments, therapeutic preparations may be enriched to provide predominantly one enantiomer of a compound (eg, of formula (1)). An enantiomerically enriched mixture may contain, for example, at least about 60 mole percent, or more preferably at least about 75 mole percent, about 90 mole percent, about 95 mole percent, or even about 99 mole percent of one enantiomer. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, and substantially free of the other enantiomer means that the substance is enriched in one enantiomer relative to the amount of the other enantiomer, e.g. less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% in a substance or mixture of compounds. For example, if a composition or compound mixture contains about 98 grams of the first enantiomer and about 2 grams of the second enantiomer, then about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer said to contain.

In certain embodiments, therapeutic preparations may be enriched to provide predominantly one diastereomer of a compound (eg, of Formula (1)). A diastereomer-enriched mixture contains, for example, at least about 60 mol percent, or more preferably at least about 75 mol percent, about 90 mol percent, about 95 mol percent, or even about 99 mol percent of one diastereomer. may contain.

The terms "optional" or "optionally" as used herein indicate that the subsequently described event or circumstance can, but need not, occur and that the description Meant to include when an event or circumstance occurs and when it does not occur. For example, "optional bond" means that the bond may or may not be present and the description includes single, double or triple bonds.

The term "purified" as used herein refers to the purity of a given compound. For example, a compound is "purified", ie, at least about 50% w/w pure, when a given compound is the major component of the composition. Thus, "purified" means at least about 50% w/w pure, at least about 60% w/w pure, at least about 70% pure, at least about 80% pure, at least about 85% pure , at least about 90% pure, at least about 92% pure, at least about 94% pure, at least about 96% pure, at least about 97% pure, at least about 98% pure, at least about 99% pure, includes at least about 99.5% pure, and at least about 99.9% pure, where "substantially pure" means at least about 97% pure, at least about 98% pure, at least about 99% pure, Including at least about 99.5% pure, and at least about 99.9% pure.

The term "salt" as used herein refers to compounds containing cations and anions, which may be formed by protonation of proton accepting moieties and/or deprotonation of proton donating moieties. can. Protonation of the proton-accepting moiety results in the formation of a cationic species whose charge is balanced by the presence of a physiological anion, while deprotonation of the proton-donating moiety results in a charge balanced by the presence of a physiological cation. It should be noted that this results in the formation of anionic species. The term "salt" in its broadest sense includes zwitterions. In some uses, the term "salt" may be limited to anion and cation pairs that are not covalently linked.

The phrase "pharmaceutically acceptable salt" means a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as Glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid , 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfate, gluconic acid, glutamic acid , salicylic acid, muconic acid, etc., or (2) the base addition salt formed with the conjugate base of any of the inorganic acids listed above, wherein the conjugate base is Na ⁺ , K ⁺ , Mg ²⁺ , Ca ²⁺ , NH _g R _4-g ⁺ wherein R is C _1-3 alkyl and g is 0, 1, 2, 3 or a base addition salt that is a number selected from four. All references to pharmaceutically acceptable salts are understood to include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein of the same acid addition salt. should.

The invention also includes useful forms of the compounds of the invention, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and/or coprecipitates.

Compounds of the invention may exist as hydrates or as solvates, wherein the compounds of the invention may contain molecules of a polar solvent, particularly water, methanol or ethanol, for example in the crystal lattice of the compound. Forms crystals containing as structural elements. The polar solvent, especially water molecules, can be present in stoichiometric or non-stoichiometric ratios with the molecules of the compound. Stoichiometric solvates, e.g., in the case of hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates Each thing is possible. The invention includes all such hydrates or solvates.

Furthermore, the compounds of the invention can exist in free form, eg as free base or as free acid, or as zwitterions, or in the form of salts. Said salt can be any salt, either organic or inorganic addition salt, in particular any pharmaceutically acceptable salt, which is customarily used in pharmacy or used, for example, to isolate or purify the compounds of the present invention. It may be an acceptable organic or inorganic addition salt.

The term "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or geriatrics) and/or other primates (e.g. cynomolgus monkeys, rhesus monkeys), commercially relevant mammals such as bovines, pigs, horses, sheep, goats, cats and/or dogs mammals, and/or birds of commercial relevance, including, for example, chickens, ducks, female geese, quail and/or turkeys.

The terms "treatment," "treating," "alleviating," and "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results, including but not limited to therapeutic and/or prophylactic benefits. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Moreover, therapeutic benefit is achieved in eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that improvement is observed in the patient even though the patient may still be afflicted with the underlying disorder. . For prophylactic benefit, the pharmaceutical compounds and/or compositions may be used in patients who are at risk of developing a particular disease or who report one or more of the physiological symptoms of the disease without a diagnosis of the disease. can be administered at any time.

As used herein, a therapeutic agent that "prevents" a disorder or condition reduces the occurrence of the disorder or condition in a treated sample relative to an untreated control sample in a statistical sample, or Refers to a compound that delays the onset of, or reduces the severity of, one or more symptoms of a disorder or condition relative to an untreated control sample.

The term "treating" includes prophylactic and/or therapeutic treatment. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration of one or more of the disclosed compositions to a subject. A treatment is prophylactic (i.e., protects a subject from developing the undesirable condition) when administered prior to clinical manifestations of the undesirable condition (e.g., a disease or other undesirable condition in the subject), whereas Treatment is therapeutic (ie, intended to diminish, ameliorate or stabilize an existing undesirable condition or its side effects) when administered after the onset of the undesirable condition.

The terms "preparation" or "dosage form" are intended to include both solid and liquid formulations of the active compound, and those skilled in the art will appreciate that the active ingredient may vary depending on the desired dose and pharmacokinetic parameters. It will be appreciated that it can be present in the preparation.

The term "excipient," as used herein, refers to chemical compounds that are used to prepare pharmaceutical compositions and are generally safe, non-toxic, and biologically or otherwise undesirable. and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.

The term "greater than zero" refers to an amount that is at the lower limit of detection by any quantitative means known in the art. Non-limiting examples of methods to quantify chemicals include chromatography (liquid LC, high performance liquid HPLC, gas G), electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photoionization. (APPI). These separation methods are coupled to mass spectrometers that identify the compounds being measured. Mass spectrometry techniques include triple quadrupole (QQQ), ion trap (IT), triple quadrupole linear ion trap (QTrap), time-of-flight (TOF), triple quadrupole time-of-flight (Q-TOF), orbitrap, and Fourier transform ion cyclotron resonance (FT-ICR). See, eg, Roskar, R. et al. Analytical Methods for Quantification of Drug Metabolites in Biological Samples 2012, pages 87-91.

The phrase "pharmaceutically acceptable" means, within the scope of sound medical judgment, any undue toxicity, irritation, allergic response or other problem or complication appropriate for use in contact with the tissue of interest. used herein to refer to compounds, materials, compositions and/or dosage forms that are commensurate with a reasonable benefit/risk ratio without

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient , solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.

The recitation of a list of elements in any definition of a variable herein includes the definition of that variable as any single element or combination (or subcombination) of the listed elements. The recitation of embodiments herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

Whenever values and ranges are provided herein, it should be understood that all values and ranges subsumed by these values and ranges are meant to be within the scope of the present invention. be. In addition, all values falling within these ranges, as well as the upper or lower limits of the range of values, are contemplated by this application.

INCORPORATION BY REFERENCE All U.S. patents and U.S. and PCT published patent applications and non-patent literature mentioned in this specification are indicated as each independent patent and publication is specifically and individually incorporated by reference. are incorporated herein by reference to the same extent as if they were incorporated herein by reference.

Compounds of formulas 1-2c shown herein below
Equation 1:

及び/又は1種以上のその塩で示される構造を有する化合物が提供され、式中、環Aは炭素環又は複素環であり、前記炭素環又は複素環は芳香族であり;
XはH又はリン酸基であり;
R₁は、H、C₁～C₆アルキル基、R₂と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換炭素環、及びR₂と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換複素環から選択され;
各R₂は独立して、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、置換又は非置換C₁～C₆アルコキシ基、カルボン酸、置換又は非置換C₁～C₆カルボキシエステル、及びR₁と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換複素環から選択され;
各R₃は独立して、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、置換又は非置換C₁～C₆アルコキシ基、カルボン酸、置換又は非置換C₁～C₆カルボキシエステル、置換又は非置換カルボキサミド、R₄と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換炭素環、及びR₄と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換複素環から選択され;
R₄は、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、置換又は非置換C₁～C₆アルコキシ基、カルボン酸、置換又は非置換C₁～C₆カルボキシエステル、置換又は非置換カルボキサミド、シアノ基、置換又は非置換スルファモイル基、芳香族又は非芳香族でもよい置換又は非置換炭素環又は複素環、R₃と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換炭素環、及びR₃と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換複素環から選択される。

and/or one or more salts thereof, wherein ring A is a carbocyclic or heterocyclic ring, and said carbocyclic or heterocyclic ring is aromatic;
X is H or a phosphate group;
R ₁ is H, a C ₁ -C ₆ alkyl group, a substituted or unsubstituted carbocyclic ring which may be aromatic or non-aromatic when taken together with R ₂ and aromatic when taken together with R ₂ or a substituted or unsubstituted heterocyclic ring which may be non-aromatic;
Each R ₂ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or from unsubstituted C ₁ -C ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, and substituted or unsubstituted heterocyclic rings which when taken together with R ₁ may be aromatic or non-aromatic selected;
Each R ₃ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C ₁ -C ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, substituted or unsubstituted carboxamides, substituted or which together with R ₄ may be aromatic or non-aromatic selected from unsubstituted carbocycle and substituted or unsubstituted heterocycle which, when taken together with _R4 , may be aromatic or non-aromatic;
R ₄ is H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C _{1 -C6} alkoxy groups, carboxylic acids, substituted or unsubstituted C1 _{- C6} carboxyesters, substituted or unsubstituted carboxamides, cyano groups, substituted or unsubstituted sulfamoyl groups, substituted or unsubstituted carbons which may be aromatic or non-aromatic ring or heterocycle; substituted or unsubstituted carbocyclic ring _, which when taken together with R3 may be aromatic or non _- aromatic; and substituted or unsubstituted carbocyclic ring, which when taken together with R3 may be aromatic or selected from substituted heterocycles;

In various embodiments, compounds of Formula 1 are represented by Formula 2:

及び/又は1種以上のその塩で表すことができ、式中、
XはH又はリン酸基であり;
R₁はH又はC₁～C₆アルキル基であり;
各R₂は独立して、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、及び置換又は非置換C₁～C₆アルコキシ基から選択され;
各R₃は独立して、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、置換又は非置換C₁～C₆アルコキシ基、カルボン酸、置換又は非置換C₁～C₆カルボキシエステル、置換又は非置換カルボキサミド、R₄と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換炭素環、及びR₄と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換複素環から選択され;
R₄は、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、置換又は非置換C₁～C₆アルコキシ基、カルボン酸、置換又は非置換C₁～C₆カルボキシエステル、置換又は非置換カルボキサミド、R₃と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換炭素環、及びR₃と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換複素環から選択される。

and/or one or more salts thereof, wherein:
X is H or a phosphate group;
R ₁ is H or a C ₁ -C ₆ alkyl group;
Each R ₂ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl groups, substituted or unsubstituted C ₁ -C ₆ alkenyl groups, substituted or unsubstituted C ₁ -C ₆ alkynyl groups, and substituted or selected from unsubstituted C1 _{- C6} alkoxy groups;
Each R ₃ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C ₁ -C ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, substituted or unsubstituted carboxamides, substituted or which together with R ₄ may be aromatic or non-aromatic selected from unsubstituted carbocycle and substituted or unsubstituted heterocycle which, when taken together with _R4 , may be aromatic or non-aromatic;
R ₄ is H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C ₁ ~C6 alkoxy groups, carboxylic acids, substituted or unsubstituted C1 _{- C6} carboxyesters, substituted or unsubstituted carboxamides _, substituted or unsubstituted carbocycles which together with R3 may be aromatic or non _- aromatic , and when taken together with R ₃ , substituted or unsubstituted heterocycle which may be aromatic or non-aromatic.

In various embodiments, the compound of Formula 2 is represented by Formula 2a:

及び/又は1種以上のその塩で表される構造を有し、式中、
R₃は独立して、H、R₄と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換炭素環、及びR₄と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換複素環から選択され;
R₄は独立して、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、置換又は非置換C₁～C₆アルコキシ基、カルボン酸、置換又は非置換C₁～C₆カルボキシエステル、置換又は非置換カルボキサミド、R₃と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換炭素環、及びR₃と一緒になった場合、芳香族又は非芳香族でもよい置換又は非置換複素環から選択され;
さらに、R₃及びR₄の少なくとも一方はHではない。

and/or one or more salts thereof, wherein
R ₃ is independently H, substituted or unsubstituted carbocyclic ring which when taken together with R ₄ may be aromatic or non-aromatic, and when taken together with R ₄ may be aromatic or non-aromatic selected from good substituted or unsubstituted heterocycles;
R ₄ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted substituted or unsubstituted C ₁ -C ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, substituted or unsubstituted carboxamides _, substituted or unsubstituted is selected from substituted carbocycle, and substituted or unsubstituted heterocycle which, when taken together with R3 _, may be aromatic or non-aromatic;
Furthermore, at _least one of R3 and _R4 is not H.

In various embodiments of Formulas 2 and 2a, R ₃ is H; R ₄ is selected from carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, and substituted or unsubstituted carboxamides. In various embodiments, X is H; _R4 is a carboxymethyl ester group.

Various embodiments include compounds 1-5, 11, 12, 14, 15, 18, 19, 21, 23, 24, 26, 27, 29, 32, and 35.

In various embodiments, the compound of Formula 2 is represented by Formula 2b:

及び/又は1種以上のその塩で表される構造を有し、式中、
R₁はH又はC₁～C₆アルキル基であり;
R₂は、H及び置換又は非置換C₁～C₆アルコキシ基から選択され;
R₃はHであり;
さらに、R₁及びR₂の少なくとも一方はHではない。

and/or one or more salts thereof, wherein
R ₁ is H or a C ₁ -C ₆ alkyl group;
R ₂ is selected from H and substituted or unsubstituted C ₁ -C ₆ alkoxy groups;
_R3 is H;
Furthermore, at least one of R ₁ and R ₂ is not H.

In various embodiments of Formulas 2 and 2b, R ₁ is a methyl group. In various embodiments of Formulas 2 and 2b, R ₂ is a methoxy group.

Various embodiments include compounds 6 and 7.

In various embodiments, the compound of Formula 2 is represented by Formula 2c:

及び/又は1種以上のその塩で表される構造を有し、式中、
R₂は、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、及び置換又は非置換C₁～C₆アルキニル基から選択され;
R₃は、H、ハロゲン、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、置換又は非置換C₁～C₆アルコキシ基、カルボン酸、置換又は非置換C₁～C₆カルボキシエステル、及び置換又は非置換カルボキサミドから選択され;
R₄は、H、置換又は非置換C₁～C₆アルキル基、置換又は非置換C₁～C₆アルケニル基、置換又は非置換C₁～C₆アルキニル基、置換又は非置換C₁～C₆アルコキシ基、カルボン酸、置換又は非置換C₁～C₆カルボキシエステル、及び置換又は非置換カルボキサミドから選択され;
さらに、R₂及びR₃の少なくとも一方はHではない。

and/or one or more salts thereof, wherein
R ₂ is selected from H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl groups, substituted or unsubstituted C ₁ -C ₆ alkenyl groups, and substituted or unsubstituted C ₁ -C ₆ alkynyl groups;
R ₃ is H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C _{1 -C6} alkoxy groups, carboxylic acids, substituted or unsubstituted C1 _{- C6} carboxyesters, and substituted or unsubstituted carboxamides;
R ₄ is H, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C ₁ -C 6 ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C1 _{- C6} carboxyesters, and substituted or unsubstituted carboxamides;
Further, at _least one of _R2 and R3 is not H.

In various embodiments of Formulas 2 and 2c, R ₂ is halogen. In various embodiments of Formulas 2 and 2c, R ₃ is selected from carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, and substituted or unsubstituted carboxamides.

Various embodiments include compounds 8, 9, 16 and 20.

Various embodiments of Formula 1 include compounds 10, 13, 17, 22, 25, 28, 30, 31, 33, 34, 36, and 37.

In various embodiments, the compound of Formula 1 is one or more salts formed with cations selected from H ⁺ , Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ , and Ca ²⁺ . and/or the salts may be acetate, trifluoromethanesulfonate (triflate), halide, trifluoroacetate, formate, H ₂ PO ₄ ⁻ , HPO ₄ ²⁻ , OH ⁻ , HSO ₄ ⁻ , SO ₄ ²⁻ , NO ₃ ⁻ , HCO ₃ ⁻ , and CO ₃ ²⁻ , and mixtures thereof. In various embodiments, the compound is zwitterionic.

The invention includes the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. In certain embodiments, salts contemplated of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkylammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine salts, benetamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts. , diethylamine salt, 2-(diethylamino)ethanol salt, ethanolamine salt, ethylenediamine salt, N-methylglucamine salt, hydrabamine salt, 1H-imidazole salt, lithium salt, L-lysine salt, magnesium salt, 4-(2- hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts and zinc salts.

In certain embodiments, the compound is a salt with an anion selected from acetate, triflate, halide, trifluoroacetate or formate. In other embodiments, if the disclosed compound is contacted with a medium, such as an aqueous medium, the anion is, for example, OH ⁻ , H ₂ PO ₄ ⁻ , HPO ₄ ²⁻ , HSO ₄ ⁻ , SO ₄ ^2- , _NO3- ^, _HCO3- ^and _CO32- ^.

In some embodiments, the disclosed compounds are in the form of negatively charged phosphates that can form salts with any suitable cation. The cation can change when the compound is isolated or transferred into a medium with different anionic species. For example, the disclosed compounds may be in the form of phosphate salts, which are pharmaceutically acceptable salts as described herein. In certain embodiments, cations may be selected from Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ and Ca ²⁺ .

Synthesis In various embodiments, a method of synthesizing the compounds disclosed herein comprises reacting an amine-containing precursor with a nicotinic acid riboside precursor under conditions conducive to condensation of said precursors, formulas 1- A method is disclosed comprising producing a compound according to 2c. In certain embodiments, compounds according to the invention may be prepared by condensing a suitable nicotinamide or related precursor with 1,2,3,5-tetraacetyl-β-D-ribofuranose. For example, see Scheme 1.

In various embodiments, the synthesis can be performed as a one-pot preparation of the crude triol with purification of the product by precipitation. In various embodiments, the synthesis can be performed as a one-pot preparation of the crude triol and purification of the product by chromatography.

Scheme 1: Preparation of triols

ある特定の実施形態において、ニコチネート出発材料は、ニコチン酸とアニリド出発材料などとの縮合により調製され得る。例えば、ニコチネートの一般的調製におけるアミド結合形成の例としてのスキーム2を参照されたい。

In certain embodiments, the nicotinate starting material can be prepared by condensation of nicotinic acid with an anilide starting material and the like. See, eg, Scheme 2 for an example of amide bond formation in the general preparation of nicotinates.

Scheme 2: Preparation of nicotinate

Compositions and Pharmaceutical Formulations Provided herein are compositions comprising one or more pharmaceutically acceptable excipients and one or more compounds and/or salts thereof, wherein the compounds are of formulas 1, 2 , 2a, 2b, and/or 2c.

Also provided herein are compositions comprising compounds of formulas 1-2c, including compounds 1-31. In some embodiments of the composition, the compound is in amorphous solid form. In other embodiments, the compound is in crystalline solid form. In some embodiments, the compound is dissolved in a solvent or carrier.

In some embodiments, pharmaceutically acceptable excipients include anti-adherents, binders, coatings, dyes, disintegrants, flavoring agents, glidants, lubricants, preservatives, sorbents, sweeteners, Syrups, elixirs, dispersants, diluents, fillers, granulating agents, coating agents, waxes, suspending agents, wetting agents, thickeners and vehicles, and combinations thereof. In some embodiments, the excipient is a solid excipient.

In some embodiments, the pharmaceutically acceptable excipient is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25% by weight of the composition. , at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% by weight. In some embodiments, the pharmaceutically acceptable excipient is at least about 20%, at least about 25%, at least about 30%, at least about 35%, or at least about 40% by weight of the composition. %, preferably at least about 30% by weight. In other embodiments, the pharmaceutically acceptable excipient is present in an amount of at least about 50% by weight of the composition.

In some embodiments, the composition is a solid selected from tablets, pills, capsules, caplets, lozenges, granules, powders, sachets, inhalable powders, chewables, flavored tablets and lozenges. form. In certain embodiments, the composition is in tablet form. In other embodiments, the composition is in the form of a hard or soft gelatin capsule.

The compounds of this invention are formulated with conventional carriers and excipients that can be selected on the basis of normal practice. Tablets may contain excipients, lubricants, fillers, binders and the like. All formulations optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Suitable excipients are also listed in the US Food and Drug Administration Inactive Ingredients Database. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

While it is possible for active pharmaceutical ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations. Formulations of the present invention, both for veterinary use and for human use, contain at least one active ingredient, as defined above, in combination with one or more acceptable carriers therefor and optionally Including with other therapeutic ingredients. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose, (2) starches such as corn starch and potato starch, (3) Cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) talc, (8) excipients such as cocoa butter and suppository waxes, (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols such as propylene glycol, (11) polyols such as glycerin, sorbitol. , mannitol and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) Pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer solution, and (21) other non-toxic compatibility used in pharmaceutical formulations substance.

Formulations of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient as a powder or granules. The active ingredient may also be administered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets contain the active ingredient in free-flowing form, e.g., powders or granules, optionally mixed with binders, lubricants, inert diluents, preservatives, surfactants, or dispersing agents, pressed by a suitable machine. It can be prepared by compressing in Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and are optionally formulated so as to provide slow or controlled release of the active ingredient therefrom.

Pharmaceutical formulations according to the invention comprise a compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, when intended for oral use, tablets, troches, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard and soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may be sweetened, flavored to provide palatable preparations. It may contain one or more agents including agents, coloring agents and preservatives. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients are, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin or Acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. be able to. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use are either as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, or the active ingredient is mixed with a water or oil medium such as peanut oil, liquid paraffin or olive oil. It can also be provided as a soft gelatin capsule.

Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally occurring phosphatides (e.g. lecithin), condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (e.g. heptadecaethyleneoxycetanol), fatty acids and hexitol anhydrides. and condensation products of ethylene oxide with partial esters derived from (eg, polyoxyethylene sorbitan monooleate). Aqueous suspensions may contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as It may also contain sucrose or saccharin. Liquid formulations may also include eye drops or other forms of delivery to the surface of the eye or to a location adjacent to it, such as the lacrimal duct. Liquid formulations may include intravenous formulations, excipients, and carriers such as saline or buffer solutions, and may have packaging or containers for such formulations, such as for injection or infusion. .

Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water contain the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. I will provide a. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients such as sweetening, flavoring and coloring agents may also be present.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans is formulated with an appropriate and convenient amount of carrier material which can vary from about 5% to about 95% (weight:weight) of the total composition. can contain from about 1 mg to about 1000 mg of active material. The pharmaceutical composition can be prepared to provide easily measurable amounts for administration.

Formulations suitable for intrapulmonary or nasal administration are administered by rapid inhalation through the nasal passages or by inhalation through the mouth to reach the alveolar sacs, eg about 0.1 to about 500 microns, eg about 0.5, It has a particle size in a range such as about 1, about 30 or about 35 microns. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents.

The formulations are presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and are freeze-dried (frozen) requiring only the addition of a sterile liquid carrier for injection, such as water, immediately prior to use. dry) can be stored. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit sub-daily dose, or an appropriate fraction thereof, of an active ingredient as recited hereinabove.

It should be understood that, in addition to the ingredients specifically described above, the formulations of this invention may include other agents conventional in the art, given the type of formulation in question; For example, those suitable for oral administration may contain flavoring agents.

In some embodiments, the amount of compound of Formulas 1-2c in the composition is about 0.001% to 100% by weight.

In some embodiments, a compound of Formulas 1-2c is the only active pharmaceutical ingredient in the composition. Alternatively, compounds of Formulas 1-2c are formulated in a composition with one or more additional active pharmaceutical ingredients. When formulated as the only active pharmaceutical ingredient, the compounds of Formulas 1-2c may be administered individually or as part of a regimen with one or more separately formulated active pharmaceutical ingredients.

When co-administered in the same formulation or as part of a regimen with one or more separately formulated active pharmaceutical ingredients, the additional active pharmaceutical ingredient is a compound in the NAD+ pathway, such as nicotinic acid (NA ), nicotinamide (Nam), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid mononucleotide (NaMN), nicotinic acid riboside (NAR), nicotinamide adenine dinucleotide (NAD ⁺ /NADH) , nicotinamide adenine dinucleotide phosphate (NADP), and nicotinic acid adenine dinucleotide (NaAD). In some embodiments, the additional active pharmaceutical ingredient is an amorphous solid. In some embodiments, the additional active pharmaceutical ingredient is a crystalline solid. In some embodiments, the additional active pharmaceutical ingredient is amorphous NMN. In some embodiments, the additional active pharmaceutical ingredient is crystalline NMN.

In some embodiments, the additional active pharmaceutical ingredients are 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4 -[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10 -dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2 -carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene -2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (bcg), bicalutamide, bleomycin, bortezomib, beta -methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone , cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridine, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane , filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, Leucovorin, Leuprolide, Leva Misol, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulphate) famoylphenylcarbamothioyl)pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus , teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine and vorinostat (SAHA).

In other embodiments, suitable chemotherapeutic agents include: FK866, ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin and vorinostat (SAHA). In other embodiments, chemotherapeutic agents include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1- Amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo- 9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4- Fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10 -dihydroanthracene-2-sulfonate, APCP, beta-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolophylline sodium 2,4-dinitrobenzenesulfonate, sumarin and tonapophylline.

Other types of chemotherapeutic agents include immuno-oncology agents such as avagovomab, adecatumumab, aftuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epiratuzumab, indoxmod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, okalatuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, mentioned.

In some embodiments, the active pharmaceutical ingredient is selected from PARP inhibitors known to repair DNA damage, such as olaparib, veliparib, niraparib, NMS-P118, talazoparib and rucaparib.

Methods of Treatment, Diseases, Disorders and Conditions A subject in need of modulation of NAD levels, including administering a compound or salt thereof, as disclosed herein, and compositions thereof, herein. Methods of modulating NAD levels in are provided.

Provided herein are methods of treating a disease or disorder associated with NAD biosynthesis comprising administering a compound or salt thereof as disclosed herein, and compositions thereof.

Provided herein are methods of using the disclosed compounds and pharmaceutical compositions thereof. The disclosed compounds and pharmaceutical compositions thereof are useful for diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular diseases, blood clotting disorders, inflammation, cancer and/or flushing, including, for example, It can be useful in a variety of therapeutic applications, including, for example, treating and/or reducing a wide variety of diseases and disorders. The method comprises administering a disclosed compound and/or pharmaceutical composition thereof to a subject in need thereof. The disclosed compounds and pharmaceutical compositions thereof may be useful for increasing or maintaining NAD levels in certain tissues or cells while decreasing NAD levels in other tissues or cells. In various embodiments, the disclosed compounds and pharmaceutical compositions thereof selectively reduce NAD levels in some tissues or cells, while reducing NAD levels to a lesser extent in other tissues or cells. can be used for

In certain embodiments, the compounds or pharmaceutical compositions as disclosed herein are used to treat or prevent a disease or condition induced or exacerbated by cellular senescence in a subject; For example, methods of reducing aging after onset, methods of extending lifespan in a subject, methods of treating or preventing diseases or conditions associated with lifespan, methods of treating or preventing diseases or conditions associated with proliferative capacity of cells, and cytotoxicity or for methods of treating or preventing diseases or conditions caused by cell death. In certain embodiments, the method does not act by reducing the incidence of a subject's life-shortening disease. In certain embodiments, the method does not act by reducing mortality caused by disease, eg, cancer.

In certain embodiments, a compound or pharmaceutical composition as disclosed herein is used to generally increase the lifespan of a subject's cells and to induce a subject's response to stress and/or to apoptosis. It can be administered to a subject to protect cells. Treating subjects with the compounds described herein can be similar to subjecting subjects to hormesis, a mild stress that is beneficial to the organism and can extend their lifespan.

The disclosed compounds and pharmaceutical compositions thereof can be administered to subjects who have recently received or are likely to receive a dose of radiation or toxin. In one embodiment, the dose of radiation or toxin is used for work-related or medical procedures, such as work at a nuclear power plant, flying an aircraft, X-rays, CAT scans, or administration of radioactive dyes for medical imaging. and in such embodiments the compound is administered as a preventive measure. In other embodiments, radiation or toxin exposure is received unintentionally, for example, as a result of an industrial accident, residence in a location of natural radiation, an act of terrorism, or an act of war involving radioactive or toxic materials. In such cases, the disclosed compounds and pharmaceutical compositions thereof are preferably administered as soon as possible after exposure to inhibit apoptosis and the subsequent development of acute radiation syndrome.

In other embodiments, the disclosed compounds and pharmaceutical compositions thereof may be useful for treating age-related disorders, such as cancer. Illustrative cancers that can be treated using the disclosed compounds and pharmaceutical compositions thereof include hormone-dependent cancers, including brain and kidney cancer, breast, prostate, testicular and ovarian cancer. , lymphoma, and leukemia. Other diseases that can be treated include autoimmune diseases such as systemic lupus erythematosus, scleroderma and arthritis, where autoimmune cells should be removed. Viral infections such as herpes, HIV, adenovirus, and HTLV-1 associated malignant and benign disorders can also be treated by administration of the disclosed compounds and pharmaceutical compositions thereof.

In some embodiments, the disclosed compounds and pharmaceutical compositions thereof treat patients suffering from neurodegenerative diseases and traumatic or mechanical injury to the central nervous system (CNS) or peripheral nervous system (PNS) can be used for Examples of neurodegenerative diseases include, but are not limited to, ataxia, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) , diffuse Lewy body disease, acanthocytosis, primary lateral sclerosis, ocular disease (ocular neuritis), chemotherapy-induced neuropathy (e.g. from vincristine, paclitaxel, bortezomib), diabetes-induced neuropathy and Friedreich's ataxia.

Administration of the disclosed compounds and pharmaceutical compositions thereof can increase insulin sensitivity and/or decrease insulin levels in a subject. A subject in need of such treatment may be a subject with insulin resistance or other prodromal symptoms of type II diabetes, a subject with type II diabetes, or a subject likely to develop any of these conditions. . For example, the subject has insulin resistance, e.g., high circulating levels of insulin and/or related conditions, e.g. Subjects may have other manifestations of Syndrome X, hypertension, atherosclerosis and lipodystrophy.

In various embodiments, disclosed herein are methods of differentially modulating nicotinamide adenine dinucleotide (NAD) levels in two or more tissues or cell types. Such methods may comprise administering a compound or composition as disclosed herein, said administering reducing NAD in a first tissue or cell type compared to a second tissue or cell type. elicit level differential responses. In various embodiments, the differential response in NAD levels is at least 10% difference in NAD levels, at least 20% difference in NAD levels, at least 30% difference in NAD levels, at least 40% difference in NAD levels , at least 50% difference in NAD levels, at least 60% difference in NAD levels, at least 70% difference in NAD levels, at least 80% difference in NAD levels, at least 90% difference in NAD levels, at least 100% difference in NAD levels, at least 200% difference in NAD levels, at least 400% difference in NAD levels, at least 500% difference in NAD levels, at least 600% difference in NAD levels, selected from at least 700% difference in NAD levels, at least 800% difference in NAD levels, at least 900% difference in NAD levels, and at least 1000% difference in NAD levels. In various embodiments, the differential response in NAD levels is at least 10%, 20%, 30%, 40%, 50% in the first tissue or cell type compared to untreated NAD levels or NAD levels before treatment. %, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% increase in NAD levels, and at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% in a second tissue or cell type compared to untreated NAD levels or NAD levels prior to treatment, A concomitant reduction in NAD levels of 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%. In various embodiments, the differential response of NAD levels is maintenance within 10% of NAD levels in said first tissue or cell type compared to untreated NAD levels, and a second at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% of NAD levels in %, 600%, 700%, 800%, 900%, or 1000% simultaneous reduction. In various embodiments, the differential response in NAD levels is at least a 10% reduction in NAD levels in a first tissue or cell type compared to untreated NAD levels, and a second A concomitant decrease in NAD levels in a tissue or cell type, wherein the decrease in the second tissue or cell type is at least 10%, 20%, 30%, 40%, 50% greater than the decrease in the first tissue or cell type. %, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% greater reduction. In various embodiments, the first tissue or cell type is normal tissue or cells and the second tissue or cell type is neoplastic or cancerous.

The methods of cancer treatment disclosed herein include treatment of individuals in need thereof. Illustrative cancers that can be treated using the disclosed compounds and pharmaceutical compositions thereof include hormone-dependent cancers, including brain and kidney cancer, breast, prostate, testicular and ovarian cancer. , lymphoma, and leukemia. In various embodiments, the cancer may be common types of cancer in men, such as lung cancer, prostate cancer, colorectal cancer and stomach cancer. In various embodiments, the cancer may be common types of cancer in women, such as breast cancer, colorectal cancer, lung cancer and cervical cancer. In various embodiments, the cancer may be skin cancer, such as melanoma, squamous cell carcinoma, or basal cell carcinoma. In various embodiments, the cancer may be a common type of cancer in children, such as acute lymphoblastic leukemia, brain tumor, or non-Hodgkin's lymphoma. In various embodiments, the methods exhibit a selective cytostatic or cytotoxic effect, wherein the effect is the growth of neoplastic or cancerous tissue or cells compared to untreated neoplastic or cancerous tissue or cells. indicated by a decrease in the viability of

The method includes situations where the first tissue or cell type is a normal tissue or cell, and the method requires treatment to promote health or increase biological activity of the first tissue or cell type. A treatment for promoting health or increasing biological activity of a first tissue or cell type in an individual. In various embodiments, treatment does not induce an increased risk of cancer diagnosis in the treated individual. Preferably, the treatment reduces the risk of cancer diagnosis in the individual receiving treatment.

Various methods include treating or suppressing cancer in an individual in need thereof, the methods comprising administering a compound or composition as described herein. include. In various embodiments, increasing or maintaining healthy tissue or cells in an individual in need thereof without increasing the risk of growing neoplastic or cancerous tissue or cells. Disclosed herein are methods of doing so, including administering a compound or composition as described herein.

In various embodiments, methods of increasing or maintaining healthy tissue or cells in an individual in need thereof while inhibiting growth of neoplastic or cancerous tissue or cells are provided. As described herein, such methods include administering a compound or composition as described herein. In various embodiments, the disclosed methods include methods of increasing or maintaining nicotinamide adenine dinucleotide (NAD) levels in at least one healthy tissue or cell type, which methods are herein described. This includes administering the described compounds or compositions to healthy tissues or cell types. In various embodiments, methods of reducing the viability of at least one cancerous tissue or cell type are described herein, wherein such methods comprise a compound or composition as described herein. , including administration to a cancerous tissue or cell type.

Further, the methods as described herein include methods of modulating the level of NAD in at least one tissue or cell type in a mixture of tissues or cell types, such methods are herein described. Including targeted delivery of a compound or composition as described to a desired tissue or cell type. In various embodiments, targeted delivery is non-systemic.

While the written description of the invention will enable any person skilled in the art to make and use what is presently considered to be the best mode thereof, one of ordinary skill in the art will appreciate the specific embodiments, methodologies herein. and will understand and appreciate the existence of variations, combinations and equivalents of the examples. The present invention, therefore, is not to be limited by the described embodiments, methods and examples, but by all embodiments and methods within the scope and spirit of the present invention.

[Example]
Synthetic Examples General Procedure A: One-pot Preparation of Crude Triols with Product Purification by Precipitation (see Example 1)

General Procedure B: One-Pot Preparation of Crude Triol and Purification of Product by Chromatography (See Example 9)

[Example 1]
compound 1
Methyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamido)benzoate.

トリメチルシリルトリフルオロメタンスルホネート(TMS-トリフレート、4.8mL、26.5mmol、1.2当量)を、無水アセトニトリル(CH₃CN、100mL)中のメチル4-(ニコチンアミド)ベンゾエート(5.9g、23mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(8.1g、25.4mmol、1.1当量)の撹拌混合物に、Ar下で5分間にわたり滴下により添加した。反応混合物を室温で1時間撹拌し、その後アリコートのHPLC分析により10%未満のニコチンアミドが存在することが示されたら、反応は完了したと決定された。反応混合物を無水MeOH(50mL)で希釈し、ロータリーエバポレータで濃縮してCH₃CNのほとんどを除去した。混合物をMeOH(100mL)で希釈し、氷浴中で冷却した。塩化チオニル(SOCl₂、5.8mL、80.5mmol、3.5当量)を滴下により添加し、反応混合物を冷蔵室内で5℃で16時間撹拌した。アリコートのHPLC分析により5%未満のモノ及びジアセテート中間体が存在することが示されたら、反応は完了したと決定された。2Lのエルレンマイヤーフラスコ中で1.3Lの十分に撹拌したMTBEに溶液を添加することにより、粗生成物を沈殿させた。沈殿固体を濾過し、大量のMTBEで洗浄した。吸引漏斗で乾燥させた後、固体を高真空下でさらに乾燥させ、生成物(7.7g、62%)を白色固体として得た。
¹H NMR (D₂O): δ 9.64 (s,1H), 9.28 (d, 1H), 9.04 (d, 1H), 8.29 (dd, 1H), 8.02 (d, 2H), 7.70 (d, 2H), 6.24 (d, 1H), 4.52 (見かけ上t, 1H), 4.46 (m, 1H), 4.04 (見かけ上dd, 1H), 3.87 (m, 4H又は5H). MS(ESI+) m/z = 389.1

Trimethylsilyl trifluoromethanesulfonate (TMS-triflate, 4.8 mL, 26.5 mmol, 1.2 equiv) was treated with methyl 4-(nicotinamido)benzoate (5.9 g, 23 mmol) and 1,2 in anhydrous acetonitrile ( _CH3CN , 100 mL). To a stirred mixture of ,3,5-tetraacetyl-β-D-ribofuranose (8.1 g, 25.4 mmol, 1.1 eq) was added dropwise over 5 min under Ar. The reaction mixture was stirred at room temperature for 1 hour, after which the reaction was determined to be complete when HPLC analysis of an aliquot showed less than 10% nicotinamide was present. The reaction mixture was diluted with anhydrous MeOH (50 mL) and concentrated on a rotary evaporator to remove most of the _CH3CN . The mixture was diluted with MeOH (100 mL) and cooled in an ice bath. Thionyl chloride (SOCl ₂ , 5.8 mL, 80.5 mmol, 3.5 eq) was added dropwise and the reaction mixture was stirred at 5° C. in the refrigerator for 16 hours. The reaction was determined to be complete when HPLC analysis of an aliquot showed less than 5% of the mono- and diacetate intermediates were present. The crude product was precipitated by adding the solution to 1.3 L of well-stirred MTBE in a 2 L Erlenmeyer flask. The precipitated solid was filtered and washed with copious amounts of MTBE. After drying on a suction funnel, the solid was further dried under high vacuum to give the product (7.7 g, 62%) as a white solid.
¹ H NMR (D ₂ O): δ 9.64 (s, 1H), 9.28 (d, 1H), 9.04 (d, 1H), 8.29 (dd, 1H), 8.02 (d, 2H), 7.70 (d, 2H ), 6.24 (d, 1H), 4.52 (apparent t, 1H), 4.46 (m, 1H), 4.04 (apparent dd, 1H), 3.87 (m, 4H or 5H). MS(ESI+) m/z = 389.1

[Example 2]
Compound 2
N-(4-Carbamoylphenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamide.

一般手順Aに従う:TMS-トリフレート(1.2当量)を、無水アセトニトリル(40mL)中のN-(4-カルバモイルフェニル)ニコチンアミド(1.1g、4.6mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。混合物を室温で2時間撹拌し、溶媒を除去した後、40mLのMeOH中の3当量のSOCl₂で処理し、次いで5℃で24時間撹拌した。混合物を元の体積の半分まで濃縮し、MTBE(50mL)を徐々に添加して生成物を沈殿させた。固体を焼結ガラス漏斗で濾過し、2×10mL分量のMeOH(-20℃まで事前に冷却)で洗浄し、続いていくつかの分量のMTBEで洗浄した。固体を高真空下で数時間乾燥させ、生成物(1.25g、49%)を白色固体として得た。
¹H NMR (D₂O): δ 9.87 (s, 1H), 9.47 (見かけ上d, 1H), 9.17 (見かけ上d, 1H), 8.36 (t, 1H), 7.94 (dd, 4H), 6.23 (d, 1H), 4.46 (m, 2H), 4.34 (m, 1H), 3.97 (ab q, 2H). MS(ESI+) m/z = 374.1

Following General Procedure A: TMS-triflate (1.2 eq.) was combined with N-(4-carbamoylphenyl)nicotinamide (1.1 g, 4.6 mmol) and 1,2,3,5-tetraacetyl in anhydrous acetonitrile (40 mL). -β-D-ribofuranose (1.1 eq.) was added to the stirring mixture. The mixture was stirred at room temperature for 2 hours and after removal of the solvent, it was treated with 3 equivalents of SOCl ₂ in 40 mL of MeOH and then stirred at 5° C. for 24 hours. The mixture was concentrated to half its original volume and MTBE (50 mL) was slowly added to precipitate the product. The solid was filtered through a sintered glass funnel and washed with 2 x 10 mL portions of MeOH (precooled to -20°C) followed by several portions of MTBE. The solid was dried under high vacuum for several hours to give the product (1.25 g, 49%) as a white solid.
¹ H NMR (D ₂ O): δ 9.87 (s, 1H), 9.47 (ap.d, 1H), 9.17 (ap.d, 1H), 8.36 (t, 1H), 7.94 (dd, 4H), 6.23. (d, 1H), 4.46 (m, 2H), 4.34 (m, 1H), 3.97 (ab q, 2H). MS(ESI+) m/z = 374.1

[Example 3]
Compound 3
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(methylcarbamoyl)phenyl)-1λ ⁴ -pyridine-3 -Carboxamide.

一般手順Bに従う:TMS-トリフレート(1.7mL、0.55mmol、1.2当量)を、無水アセトニトリル(40mL)中のN-(4(メチルカルバモイルフェニル)ニコチンアミド(1.1g、0.46mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の2時間の撹拌混合物に添加した。その後の後処理及びMeOH中の3当量のSOCl₂での処理、続いて5℃で24時間の撹拌により、研和後に粗生成物を半固体物質として得た。材料をDCM中最低10%のMeOHに溶解し、40gのISCO自動クロマトグラフィーカートリッジに投入した。DCM中5%MeOHからDCM中30%MeOHの勾配溶出により、生成物(1.1g、62%)を白色固体として得た。
¹NMR (D₂O): δ 11.6 (s, 1H), 9.79 (s, 1H), 9.46 (d, 2H), 9.27 (d, 2H), 8.47 (m, 1H), 8.41 (t, 1H), 7.92 (dd, 4H), 6.25 (d, 1H), 4.40 (t, 1H), 4.27 (m, 1H), 4.18 (t, 1H), 3.79 (ab q, 2H), 2.78 (s, 3H). MS(ESI+) m/z = 388.1

According to general procedure B: TMS-triflate (1.7 mL, 0.55 mmol, 1.2 eq) was added to N-(4(methylcarbamoylphenyl)nicotinamide (1.1 g, 0.46 mmol) and 1,2 in anhydrous acetonitrile (40 mL). ,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq.) was added to a stirred mixture for ₂ hours, followed by work-up and treatment with 3 eq. Stirring for 24 h gave the crude product as a semi-solid material after trituration.The material was dissolved in a minimum of 10% MeOH in DCM and loaded onto a 40 g ISCO autochromatography cartridge.From 5% MeOH in DCM. Gradient elution of 30% MeOH in DCM gave the product (1.1 g, 62%) as a white solid.
¹ NMR ₍ D2O): δ 11.6 (s, 1H), 9.79 (s, 1H), 9.46 (d, 2H), 9.27 (d, 2H), 8.47 (m, 1H), 8.41 (t, 1H) , 7.92 (dd, 4H), 6.25 (d, 1H), 4.40 (t, 1H), 4.27 (m, 1H), 4.18 (t, 1H), 3.79 (ab q, 2H), 2.78 (s, 3H) .MS(ESI+) m/z = 388.1

[Example 4]
Compound 4
((2R,3S,4R,5R)-3,4-dihydroxy-5-(3-((4-(methoxycarbonyl)phenyl)carbamoyl)-1λ ⁴ -pyridin-1-yl)tetrahydrofuran-2-yl) methyl hydrogen phosphate.

乾燥100mLフラスコに、2g(4.1mmol)の化合物1を入れた。フラスコをアルゴンでフラッシュし、10mLのリン酸トリメチルを添加した。得られた溶液を0℃に冷却し、POCl₃(1.25g、8.2mmol、2当量)で処理した。フラスコを密閉し、冷凍庫内で-10℃で静置した。2.5時間後、均質溶液をトリエチルアミン(206mg、2.0mmol)で数分間にわたり処理し、冷凍庫内で一晩静置した。反応混合物を氷浴中で冷却し、十分に撹拌した懸濁液を水(1.5g、82mmol)で数分間にわたり処理し、続いて固体NaHCO₃(2.4g、28.7mmol)で処理し、撹拌を0℃で90分間継続した。反応混合物を、33mmolの90%ギ酸を含有する100mLのCH₃CNで処理し、白色固体を生成した。固体を濾過により回収し、CH₃CNで洗浄し、高真空下に置いて、粗生成物をオフホワイトの固体(3.7g)として得た。この材料を、50gのアミノプロピル官能化シリカを含有するカラムで、中圧クロマトグラフィーにより精製した。生成物を、100mMのギ酸を含有する25mLの60%/40% MeOH-CH₃CNに溶解し、カラムを同じ溶媒混合物で平衡化した。生成物含有画分を合わせて濃縮し、水(3×25mL)から共蒸発させ、冷凍及び凍結乾燥させて、生成物(300mg、16%)を白色固体として得た。
¹H NMR (D₂O): δ 9.4 (s, 1H), 9.2 (m, 1H), 8.9 (d, 1H), 8.2 (m, 1H), 7.9 (d, 2H), 7.6 (d, 2H), 6.1 (d, 1H), 4.6 (m, 1H), 4.5 (m, 1H), 4.4 (q, 1H), 4.2 (dq, 1H), 4.1 (dq, 1H), 3.8 (s, 3H). ³¹P NMR (D₂O): 0.24 ppm. MS(ESI+) m/z = 468.1

A dry 100 mL flask was charged with 2 g (4.1 mmol) of Compound 1. The flask was flushed with argon and 10 mL of trimethyl phosphate was added. The resulting solution was cooled to 0° C. and treated with POCl ₃ (1.25 g, 8.2 mmol, 2 eq). The flask was sealed and placed in a freezer at -10°C. After 2.5 hours, the homogenous solution was treated with triethylamine (206 mg, 2.0 mmol) over several minutes and left in the freezer overnight. The reaction mixture was cooled in an ice bath and the well-stirred suspension was treated with water (1.5 g, 82 mmol) over several minutes followed by solid NaHCO ₃ (2.4 g, 28.7 mmol) and stirring was discontinued. Continued at 0°C for 90 minutes. The reaction mixture was treated with 100 mL of CH ₃ CN containing 33 mmol of 90% formic acid to yield a white solid. The solid was collected by filtration, washed with _CH3CN and placed under high vacuum to give the crude product as an off-white solid (3.7g). This material was purified by medium pressure chromatography on a column containing 50 g of aminopropyl functionalized silica. The product was dissolved in 25 mL of 60%/40% MeOH- _CH3CN containing 100 mM formic acid and the column was equilibrated with the same solvent mixture. The product-containing fractions were combined, concentrated, co-evaporated from water (3 x 25 mL), frozen and lyophilized to give the product (300 mg, 16%) as a white solid.
¹ H NMR (D ₂ O): δ 9.4 (s, 1H), 9.2 (m, 1H), 8.9 (d, 1H), 8.2 (m, 1H), 7.9 (d, 2H), 7.6 (d, 2H ), 6.1 (d, 1H), 4.6 (m, 1H), 4.5 (m, 1H), 4.4 (q, 1H), 4.2 (dq, 1H), 4.1 (dq, 1H), 3.8 (s, 3H) ^31P NMR ₍ D2O): 0.24 ppm. MS(ESI+) m/z = 468.1.

[Example 5]
compound 5
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(1-oxo-1,3-dihydroisobenzofuran-5-yl )-1λ ⁴ -pyridine-3-carboxamide.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、無水アセトニトリル(40mL)中のN-(1-オキソ-1,3-ジヒドロイソベンゾフラン-5-イル)ニコチンアミド(1.2g、4.7mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の2時間の撹拌混合物に添加した。溶媒の蒸発及びMeOH(40mL)中のSOCl₂(3当量)による処理、続いて5℃で24時間の撹拌及びその後の後処理により、粗生成物を半固体物質として得た。粗生成物をDCM中最低5%のMeOHに溶解し、24gのISCOカートリッジに投入した。DCM中5%MeOHからDCM中30%MeOHの勾配溶出により、生成物(1.75g、67%)を白色固体として得た。
¹H NMR (D₂O): δ 9.63 (s, 1H), 9.26 (d, 1H), 9.04 (d, 1H), 8.28 (t, 1H), 7.86 (s, 1H), 7.75 (d, 1H), 7.59 (d, 1H), 6.23 (d, 1H), 4.52 (t, 1H), 4.44 (m, 1H), 4.34 (t, 1H), 3.95 (ab q, 2H). MS(ESI+) m/z = 387.1

According to general procedure B: TMS-triflate (1.2 eq.) to N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)nicotinamide (1.2 g, 4.7 mmol) in anhydrous acetonitrile (40 mL). and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq.) were added to a stirred mixture for 2 hours. Evaporation of the solvent and treatment with SOCl ₂ (3 eq.) in MeOH (40 mL), followed by stirring at 5° C. for 24 h and subsequent work-up gave the crude product as a semi-solid material. The crude product was dissolved in a minimum of 5% MeOH in DCM and loaded onto a 24g ISCO cartridge. Gradient elution from 5% MeOH in DCM to 30% MeOH in DCM gave the product (1.75 g, 67%) as a white solid.
¹ H NMR (D ₂ O): δ 9.63 (s, 1H), 9.26 (d, 1H), 9.04 (d, 1H), 8.28 (t, 1H), 7.86 (s, 1H), 7.75 (d, 1H ), 7.59 (d, 1H), 6.23 (d, 1H), 4.52 (t, 1H), 4.44 (m, 1H), 4.34 (t, 1H), 3.95 (ab q, 2H). MS(ESI+) m /z = 387.1

[Example 6]
compound 6
Methyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-methyl-1λ ⁴ -pyridine-3-carboxamido)benzoate .

乾燥100mL RBに3.2gのメチル4-(N-メチルニコチンアミド)ベンゾエート(11.8mmol)を入れ、フラスコをアルゴンでフラッシュした。これをアルゴン流下で35mLの無水ジオキサンに溶解し、3.8gのリボーステトラアセテート(11.8mmol)で処理した。得られた溶液を氷水で短時間冷却し、3.2gのTMS-トリフレート(14.2mmol)で処理し、周囲温度まで温め、撹拌した。2.5時間後、反応を約90%完了まで進めた。ロータリーエバポレーションにより溶媒を除去し、残渣を50mLのDCMに吸収させた。これを飽和NaHCO₃及びブラインで洗浄した。水層をDCMで逆抽出し、有機層を合わせ、Na₂SO₄で乾燥し、濾過し、高真空下で蒸発させ、6.9gのオフホワイトの泡を得た。これを、120gのシリカカートリッジを使用して、DCM中0～15%のMeOHの勾配で中圧LCシステムで精製した。生成物画分を単離してプールし、ストリッピングし、高真空下に置いて、トリアセテート5.6g(70%)を得た。
¹H NMR (CDCl₃): δ 9.3 (bd s, 1H); 9.2 (d, 1H); 8.0 (d, 2H); 7.3 (d, 2H); 6.6 (d, 1H); 5.3 (m, 1H); 5.2 (m, 1H); 4.7 (m, 1H); 4.5 (dd, 1H); 4.4 (dd, 1H); 3.9 (s, 3H); 3.6 (s, 3H); 2.2 (s, 3H); 2.1 (s, 3H); 2.0 (s, 3H).

A dry 100 mL RB was charged with 3.2 g of methyl 4-(N-methylnicotinamido)benzoate (11.8 mmol) and the flask was flushed with argon. This was dissolved in 35 mL of anhydrous dioxane under a stream of argon and treated with 3.8 g of ribose tetraacetate (11.8 mmol). The resulting solution was briefly cooled with ice water, treated with 3.2 g of TMS-triflate (14.2 mmol), warmed to ambient temperature and stirred. After 2.5 hours, the reaction proceeded to about 90% completion. Solvent was removed by rotary evaporation and the residue was taken up in 50 mL DCM. This was washed with saturated NaHCO ₃ and brine. The aqueous layer was back extracted with DCM and the organic layers _were combined, dried over _Na2SO4 , filtered and evaporated under high vacuum to give 6.9g of off-white foam. This was purified on a medium pressure LC system using a 120 g silica cartridge and a gradient of 0-15% MeOH in DCM. Product fractions were isolated, pooled, stripped and placed under high vacuum to give 5.6 g (70%) of triacetate.
¹ H NMR (CDCl ₃ ): δ 9.3 (bd s, 1H); 9.2 (d, 1H); 8.0 (d, 2H); 7.3 (d, 2H); 6.6 (d, 1H); ); 5.2 (m, 1H); 4.7 (m, 1H); 4.5 (dd, 1H); 4.4 (dd, 1H); 2.1 (s, 3H); 2.0 (s, 3H).

A 250 mL RB was charged with 5.6 g of the above triacetate (8.2 mmol) and the flask was flushed with argon. This was dissolved in 75 mL of anhydrous MeOH and the resulting solution was cooled on ice and treated dropwise with 2.94 g of SOCl ₂ (24.7 mmol). The closed reaction vessel was placed in a refrigerator at 10°C. After 18 hours the solvent was removed in vacuo and the residue was triturated with MTBE then placed under high vacuum to give 4.7g as a white solid. This was purified on a 40g silica ISCO cartridge using a gradient of 0-15% MeOH in DCM. Product fractions were pooled and stripped to give 2.5g as an off-white foam.
¹ H NMR (CDCl ₃ ): δ 9.0 (d, 1H); 8.1 (d, 1H); 7.8 (m, 3H); 7.2 (d, 2H); 5.8 (d, 1H); 4.1 (d, 2H); 3.8-3.6 (4H); 3.4 (s, 3H); 3.2 (s, 3H).

[Example 7]
compound 7
Methyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamide)-3-methoxy- Benzoate.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、無水アセトニトリル(40mL)中のメチル3-メトキシ-4-(ニコチンアミド)ベンゾエート(1.6g、5.63mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加し、得られた混合物を2時間撹拌した。前述の通りの後処理及びその後のMeOH中3当量のSOCl₂での処理、続いて5℃で24時間の撹拌により、研和後に粗生成物を半固体物質として得た。DCMからDCM中30%MeOHの勾配で溶出するISCO(40gのカートリッジ)を使用して粗生成物を精製して、生成物(715mg、23%)をオフホワイトの固体として得た。
¹H NMR (CD₃OD): δ 9.84 (s, 1H), 9.67 (d, 1H), 9.12 (d, 1H), 8.31-8.36 (m, 2H), 7.72-7.74 (m, 2H), 6.25 (d, 1H), 4.42-4.52 (m, 2H), 4.36 (m, 1H), 4.04 (s, 3H), 3.96 (ab q, 2H), 3.91 (s, 3H). MS(ESI+) m/z = 419.1

Following General Procedure B: TMS-triflate (1.2 eq.) was combined with methyl 3-methoxy-4-(nicotinamido)benzoate (1.6 g, 5.63 mmol) and 1,2,3,5- Tetraacetyl-β-D-ribofuranose (1.1 eq) was added to the stirring mixture and the resulting mixture was stirred for 2 hours. Workup as previously described followed by treatment with 3 equivalents of SOCl ₂ in MeOH, followed by stirring at 5° C. for 24 h gave the crude product as a semi-solid material after trituration. The crude product was purified using ISCO (40 g cartridge) eluting with a gradient of DCM to 30% MeOH in DCM to give the product (715 mg, 23%) as an off-white solid.
¹ H NMR (CD ₃ OD): δ 9.84 (s, 1H), 9.67 (d, 1H), 9.12 (d, 1H), 8.31-8.36 (m, 2H), 7.72-7.74 (m, 2H), 6.25 (d, 1H), 4.42-4.52 (m, 2H), 4.36 (m, 1H), 4.04 (s, 3H), 3.96 (ab q, 2H), 3.91 (s, 3H). MS(ESI+) m/ z = 419.1

[Example 8]
compound 8
Methyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamide)-3-fluorobenzoate .

一般手順Bに従う:TMS-トリフレート(1.2当量)を、無水アセトニトリル(40mL)中のメチル3-フルオロ-4-(ニコチンアミド)ベンゾエート(610mg、2.31mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(800mg、2.5mmol、1.1当量)の撹拌混合物に添加し、混合物を周囲温度で2時間撹拌した。溶媒を減圧下で蒸発させ、残渣をMeOH中3当量のSOCl₂で処理し、続いて5℃で24時間撹拌した。前述の通りの後処理によって、DCMとの共蒸発による過剰のHClの除去後に粗生成物を半固体物質として得た。DCMからDCM中30%MeOHの勾配で溶出するISCO(24gのカートリッジ)で粗生成物を精製して、生成物(400mg、31%)を淡褐色固体として得た。
¹H NMR (CD₃CN): δ 9.66 (S, 1H), 9.30 (br s, 1H), 9.26 (d, 1H), 8.98 (d, 1H), 8.26 (t, 2H), 7.93 (d, 1H), 7.87 (d, 1H), 6.14 (d, 1H), 4.47 (t, 1H), 4.13 (m, 1H), 3.94 (ab q, 2H, 3.92 (s, 1H). MS(ESI+) m/z = 407.1

Following General Procedure B: TMS-triflate (1.2 eq.) was combined with methyl 3-fluoro-4-(nicotinamido)benzoate (610 mg, 2.31 mmol) and 1,2,3,5-tetramethyl 3-fluoro-4-(nicotinamido)benzoate (610 mg, 2.31 mmol) in anhydrous acetonitrile (40 mL). Acetyl-β-D-ribofuranose (800 mg, 2.5 mmol, 1.1 eq) was added to the stirred mixture and the mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was treated with 3 equivalents of SOCl ₂ in MeOH followed by stirring at 5° C. for 24 hours. Workup as previously described gave the crude product as a semi-solid material after removal of excess HCl by co-evaporation with DCM. The crude product was purified by ISCO (24g cartridge) eluting with a gradient of DCM to 30% MeOH in DCM to give the product (400mg, 31%) as a light brown solid.
¹ H NMR (CD ₃ CN): δ 9.66 (S, 1H), 9.30 (br s, 1H), 9.26 (d, 1H), 8.98 (d, 1H), 8.26 (t, 2H), 7.93 (d, 1H), 7.87 (d, 1H), 6.14 (d, 1H), 4.47 (t, 1H), 4.13 (m, 1H), 3.94 (ab q, 2H, 3.92 (s, 1H). MS(ESI+) m /z = 407.1

[Example 9]
compound 9
Ethyl 3-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamido)benzoate.

TMS-トリフレート(2.9mL、15.7mmol、1.2当量)を、無水DCM(80mL)中のエチル3-(ニコチンアミド)ベンゾエート(3.85g、14.3mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(8.1g、25.4mmol、1.1当量)の撹拌混合物に、Ar下で滴下により添加した。反応混合物を室温で1時間撹拌し、その後、ニコチンアミドの不溶性に起因して、HPLC分析により反応の10%のみが完了したことが判明した。反応混合物を無水ジオキサン(30mL)で希釈し、追加のTMS-トリフレート(3.0mL、1.1当量)を添加した。反応混合物を1時間撹拌し、その時点でHPLC分析により反応が完了したことが判明した。混合物をロータリーエバポレータで約20mLまで濃縮し、無水EtOH(50mL)で希釈し、氷浴中で冷却し、SOCl₂(4.2mL、57.3mmol、4当量)で滴下により処理した。混合物を冷蔵室内で5℃で3日間撹拌し、次いでロータリーエバポレータで約30mLまで濃縮し、MTBEで研和して、粗生成物を半固体物質として沈殿させた。生成物をMTBEでさらに研和して、オフホワイトの固体(2g)を得た。1gのこの材料を、24gのシリカゲルカートリッジを使用し、DCM中最低5%のMeOHを添加して、ISCO Combi Flash(登録商標)自動クロマトグラフィーシステムで精製した。溶出は、DCM中5%MeOHからDCM中30%MeOHの勾配を使用して行った。純粋な画分をプール及び濃縮し、次いでDCMと同時ストリッピングして、高真空下に数時間置いた後、純粋な生成物(700mg、全体的収率24%)を白色固体として得た。
¹H NMR (D₂O): δ 9.64 (s, 1H), 9.30 (d, 1H), 9.04 (d, 1H), 8.42 (s, 1H), 8.27 (見かけ上t, 1H), 7.94 (d, 1H), 7.85 (d, 1H), 7.85 (d, 1H), 7.55 (t, 1H), 6.16 (d, 1H), 4.46 (見かけ上t, 1H), 4.33-4.43 (m, 2又は3H), 4.31 (見かけ上t, 1H), 3.92 (ab q, 2H), 1.97 (q, 2H). MS(ESI+) m/z = 403.1

TMS-triflate (2.9 mL, 15.7 mmol, 1.2 eq) was combined with ethyl 3-(nicotinamido)benzoate (3.85 g, 14.3 mmol) and 1,2,3,5-tetraacetyl- in anhydrous DCM (80 mL). To a stirred mixture of β-D-ribofuranose (8.1 g, 25.4 mmol, 1.1 eq) was added dropwise under Ar. The reaction mixture was stirred at room temperature for 1 hour, after which HPLC analysis showed only 10% of the reaction was complete due to the insolubility of nicotinamide. The reaction mixture was diluted with anhydrous dioxane (30 mL) and additional TMS-triflate (3.0 mL, 1.1 eq) was added. The reaction mixture was stirred for 1 hour, at which time HPLC analysis indicated the reaction was complete. The mixture was concentrated on a rotary evaporator to approximately 20 mL, diluted with absolute EtOH (50 mL), cooled in an ice bath, and treated dropwise with SOCl ₂ (4.2 mL, 57.3 mmol, 4 eq). The mixture was stirred in the refrigerator at 5° C. for 3 days, then concentrated on a rotary evaporator to approximately 30 mL and triturated with MTBE to precipitate the crude product as a semi-solid material. The product was further triturated with MTBE to give an off-white solid (2g). 1 g of this material was purified on an ISCO Combi Flash® automated chromatography system using a 24 g silica gel cartridge and adding a minimum of 5% MeOH in DCM. Elution was performed using a gradient from 5% MeOH in DCM to 30% MeOH in DCM. Pure fractions were pooled and concentrated, then co-stripped with DCM to give the pure product (700 mg, 24% overall yield) as a white solid after several hours under high vacuum.
¹ H NMR (D ₂ O): δ 9.64 (s, 1H), 9.30 (d, 1H), 9.04 (d, 1H), 8.42 (s, 1H), 8.27 (apparent t, 1H), 7.94 (d , 1H), 7.85 (d, 1H), 7.85 (d, 1H), 7.55 (t, 1H), 6.16 (d, 1H), 4.46 (apparent t, 1H), 4.33-4.43 (m, 2 or 3H ), 4.31 (apparent t, 1H), 3.92 (ab q, 2H), 1.97 (q, 2H). MS(ESI+) m/z = 403.1

[Example 10]
compound 10
Ethyl 2-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamido)benzoate.

トリメチルシリルトリフルオロメタンスルホネート(TMS-トリフレート、3.3mL、17.8mmol、1.2当量)を、無水DCM(35mL)中のメチル2-(ニコチンアミド)ベンゾエート(3.8g、14.8mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(5.2g、16.3mmol、1.1当量)の撹拌混合物に、Ar下で5分間にわたり滴下により添加した。反応混合物を周囲温度で1.5時間撹拌し、HPLCにより反応が完了したことを決定した。混合物を氷浴中で冷却し、無水MeOH(50mL)で希釈し、塩化チオニル(SOCl₂、3.22mL、44.4mmol、3当量)を滴下により添加した。溶液を冷蔵室内で5℃で24時間静置した。混合物をロータリーエバポレータで約20mLまで濃縮し、100mLのMTBEの添加により生成物を沈殿させた。溶液をデカンテーションした後、残渣をMTBEで2回研和して、淡褐色固体を得た。クロマトグラフィーにより2gの試料の精製を試みたが成功せず、カラム上で生成物が分解した。1.2gの固体を無水EtOH(10mL)に溶解し、40mLのMTBEの添加により生成物を沈殿させた。MTBEでの連続的研和後、濾過により固体を収集し、MTBEで洗浄した。高真空下で一晩乾燥させた後、生成物(780mg)を95%の純度のオフホワイトの固体として得た。
¹H NMR (DMSO-d₆): δ 11.74 (s, 1H), 9.80 (s, 1H), 9.52 (d, 1H), 9.13 (d, 1H), 8.45 (t, 1H), 8.21 (d, 1H), 8.03 (d, 1H), 7.74 (t, 1H), 7.38 (t, 1H), 6.29 (d, 1H), 4.38 (t, 1H), 4.23 (m, 1H), 3.88 (s, 3H). MS(ESI+) m/z = 389.1

Trimethylsilyl trifluoromethanesulfonate (TMS-triflate, 3.3 mL, 17.8 mmol, 1.2 eq) was treated with methyl 2-(nicotinamido)benzoate (3.8 g, 14.8 mmol) and 1,2,3, in anhydrous DCM (35 mL). To a stirred mixture of 5-tetraacetyl-β-D-ribofuranose (5.2 g, 16.3 mmol, 1.1 eq) was added dropwise over 5 minutes under Ar. The reaction mixture was stirred at ambient temperature for 1.5 hours and determined to be complete by HPLC. The mixture was cooled in an ice bath, diluted with anhydrous MeOH (50 mL) and thionyl chloride (SOCl ₂ , 3.22 mL, 44.4 mmol, 3 eq) was added dropwise. The solution was allowed to stand at 5°C in a refrigerator for 24 hours. The mixture was concentrated to approximately 20 mL on a rotary evaporator and the product was precipitated by the addition of 100 mL of MTBE. After decanting the solution, the residue was triturated twice with MTBE to give a light brown solid. Attempts to purify a 2 g sample by chromatography were unsuccessful and the product decomposed on the column. 1.2 g of solid was dissolved in absolute EtOH (10 mL) and the product was precipitated by the addition of 40 mL of MTBE. After successive trituration with MTBE, solids were collected by filtration and washed with MTBE. After drying overnight under high vacuum, the product (780 mg) was obtained as an off-white solid with 95% purity.
¹ H NMR (DMSO-d ₆ ): δ 11.74 (s, 1H), 9.80 (s, 1H), 9.52 (d, 1H), 9.13 (d, 1H), 8.45 (t, 1H), 8.21 (d, 1H), 8.03 (d, 1H), 7.74 (t, 1H), 7.38 (t, 1H), 6.29 (d, 1H), 4.38 (t, 1H), 4.23 (m, 1H), 3.88 (s, 3H ). MS(ESI+) m/z = 389.1

[Example 11]
compound 11
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(hydroxymethyl)phenyl)-1λ ⁴ -pyridine-3 -Carboxamide.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、無水CH₃CN(20mL)中のN-(4-(メトキシメチル)フェニル)ニコチンアミド(0.50g、1.95mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で2時間撹拌した後、溶媒を蒸発させ、残渣を無水MeOH(20mL)に吸収させ、氷浴中で冷却し、SOCl₂(3.5当量)で処理した。5℃で16時間撹拌した後、HPLC分析では約20%のモノアセテート中間体がまだ存在することが示されたため、追加のSOCl₂(1当量)を添加し、5℃で8時間撹拌を継続した。後処理及びISCOでの粗生成物の精製後、生成物(405mg、13%)が淡黄色固体として単離された。
¹H NMR (D₂O): δ 9.63 (s, 1H), 9.25 (d, 1H), 9.02 (d, 1H), 8.26 (見かけ上t, 1H), 7.54 (m, 2H), 7.43 (d, 1H), 7.34 (d, 1H), 6.24 (d, 1H), 4.50 (t, 1H), 4.46 (m, 1H), 4.35 (s, 2H), 3.95 (ab q, 2H). MS(ESI+) m/z = 361.1

According to general procedure B: TMS-triflate (1.2 equiv.) was treated with N-(4-(methoxymethyl)phenyl)nicotinamide (0.50 g, 1.95 mmol) and 1,2,3 in anhydrous _CH3CN (20 mL). ,5-Tetraacetyl-β-D-ribofuranose (1.1 eq) was added to a stirred mixture. After stirring for 2 hours at ambient temperature the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL), cooled in an ice bath and treated with SOCl ₂ (3.5 eq). After stirring for 16 hours at 5°C, HPLC analysis indicated ~20% of the monoacetate intermediate was still present, so additional SOCl ₂ (1 eq) was added and stirring continued for 8 hours at 5°C. did. After work-up and ISCO purification of the crude product, the product (405 mg, 13%) was isolated as a pale yellow solid.
¹ H NMR (D ₂ O): δ 9.63 (s, 1H), 9.25 (d, 1H), 9.02 (d, 1H), 8.26 (apparent t, 1H), 7.54 (m, 2H), 7.43 (d , 1H), 7.34 (d, 1H), 6.24 (d, 1H), 4.50 (t, 1H), 4.46 (m, 1H), 4.35 (s, 2H), 3.95 (ab q, 2H). ) m/z = 361.1

[Example 12]
Compound 12
N-(4-(Diethylcarbamoyl)phenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3 -Carboxamide.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、DCM(50mL)中のN-(4-(ジエチルカルバモイル)フェニル)ニコチンアミド(1.4g、4.7mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.15当量)の撹拌混合物に添加し、続いて3時間撹拌した。MeOH中のSOCl₂(3当量)によるその後の処理及び5℃で16時間の撹拌により、前述の通りの後処理後に粗生成物を半固体物質として得た。残渣をDCM中最低15%のMeOHに吸収させ、DCM中10%MeOHからDCM中40%MeOHの勾配で溶出する40gのISCOカラムに投入して、生成物(1.15g、57%)をオフホワイトの固体として得た。
¹H NMR (D₂O): δ 9.67 (s, 1H), 9.27 (d, 1H), 9.05 (d, 1H), 8.29 (t, 1H), 7.67 (d, 2H), 7.46 (d, 2H), 6.24 (d, 1H), 4.53 ( 見かけ上t, 1H), 4.46 (m, 1H), 4.36 (t, 1H), 3.95 (ab q, 2H), 3.53 (q, 2H), 3.29 (q, 2H), 1.23 (t, 3H), 1.09 (t, 3H). MS(ESI+) m/z = 430.2

Following General Procedure B: TMS-triflate (1.2 eq) was combined with N-(4-(diethylcarbamoyl)phenyl)nicotinamide (1.4 g, 4.7 mmol) and 1,2,3,5- Tetraacetyl-β-D-ribofuranose (1.15 eq) was added to a stirred mixture, followed by stirring for 3 hours. Subsequent treatment with SOCl ₂ (3 eq) in MeOH and stirring at 5° C. for 16 h gave the crude product as a semi-solid material after work-up as previously described. The residue was taken up in a minimum of 15% MeOH in DCM and loaded onto a 40 g ISCO column eluting with a gradient of 10% MeOH in DCM to 40% MeOH in DCM to give an off-white product (1.15 g, 57%). obtained as a solid.
¹ H NMR (D ₂ O): δ 9.67 (s, 1H), 9.27 (d, 1H), 9.05 (d, 1H), 8.29 (t, 1H), 7.67 (d, 2H), 7.46 (d, 2H ), 6.24 (d, 1H), 4.53 (apparent t, 1H), 4.46 (m, 1H), 4.36 (t, 1H), 3.95 (ab q, 2H), 3.53 (q, 2H), 3.29 (q , 2H), 1.23 (t, 3H), 1.09 (t, 3H). MS(ESI+) m/z = 430.2

[Example 13]
Compound 13
N-(4-Cyanophenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamide.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、DCM(40mL)中のN-(4-シアノフェニル)ニコチンアミド(1.5g、5.63mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加し、続いて周囲温度で3時間撹拌した。溶媒の蒸発に続くMeOH中のSOCl₂(3当量)による処理及び5℃で16時間の撹拌により、前述の通りの後処理後に粗生成物を半固体物質として得た。残渣をDCM中最低20%のMeOHに吸収させ、DCM中10%MeOHからDCM中40%MeOHの勾配で溶出する40gのISCOカラムに投入して、1.15g(57%)の純粋な生成物をオフホワイトの固体として得た。
¹H NMR (D₂O): δ 9.66 (s, 1H), 9.27 (d, 1H), 9.04 (d, 1H), 8.28 (t, 1H), 7.75 (m, 4H), 6.25 (d, 1H), 4.52 (t, 1H), 4.46 (m, 1H), 4.34 (見かけ上t, 1H), 4.03 (dd, 1H), 3.95 (ab q, 2H). MS(ESI+) m/z = 356.1

Following General Procedure B: TMS-triflate (1.2 eq) was combined with N-(4-cyanophenyl)nicotinamide (1.5 g, 5.63 mmol) and 1,2,3,5-tetraacetyl- β-D-ribofuranose (1.1 eq) was added to a stirred mixture, followed by stirring at ambient temperature for 3 hours. Evaporation of the solvent followed by treatment with SOCl ₂ (3 eq.) in MeOH and stirring at 5° C. for 16 h gave the crude product as a semi-solid material after work-up as previously described. The residue was taken up in a minimum of 20% MeOH in DCM and loaded onto a 40 g ISCO column eluting with a gradient of 10% MeOH in DCM to 40% MeOH in DCM yielding 1.15 g (57%) of pure product. Obtained as an off-white solid.
¹ H NMR (D ₂ O): δ 9.66 (s, 1H), 9.27 (d, 1H), 9.04 (d, 1H), 8.28 (t, 1H), 7.75 (m, 4H), 6.25 (d, 1H ), 4.52 (t, 1H), 4.46 (m, 1H), 4.34 (apparent t, 1H), 4.03 (dd, 1H), 3.95 (ab q, 2H). MS(ESI+) m/z = 356.1

[Example 14]
Compound 14
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(trifluoromethyl)phenyl)-1λ ⁴ -pyridine- 3-carboxamide.

一般手順Bに従う:TMS-トリフレート(1.5mL、8.04mmol、1.2当量)を、DCM(40mL)中のN-(4-(トリフルオロメチル)フェニル)ニコチンアミド(1.5g、6.7mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(2.4g、7.4mmol、1.1当量)の撹拌混合物に添加した。MeOH中のSOCl₂(3当量)によるその後の処理及び5℃で16時間の撹拌、続いて前述の通りの後処理により、粗生成物をオフホワイトの固体として得た。この材料の半分を、ISCO(40gのカートリッジ、DCMからDCM中30%MeOHの勾配で溶出)でクロマトグラフィー処理して、生成物(300mg)を白色固体として得た。
¹H NMR (D₂O): δ 9.66 (s, 1H), 9.27 (d, 1H), 9.04 (d, 1H), 8.28 (t, 1H), 7.75 (m, 4H), 6.25 (d, 1H), 4.52 (t, 1H), 4.46 (m, 1H), 4.34 (見かけ上t, 1H), 4.03 (dd, 1H), 3.95 (ab q, 2H). MS(ESI+) m/z = 399.1

According to general procedure B: TMS-triflate (1.5 mL, 8.04 mmol, 1.2 eq) is combined with N-(4-(trifluoromethyl)phenyl)nicotinamide (1.5 g, 6.7 mmol) and 1 in DCM (40 mL). ,2,3,5-tetraacetyl-β-D-ribofuranose (2.4 g, 7.4 mmol, 1.1 eq) was added to a stirred mixture. Subsequent treatment with SOCl ₂ (3 eq.) in MeOH and stirring at 5° C. for 16 h, followed by workup as previously described gave the crude product as an off-white solid. Half of this material was chromatographed by ISCO (40 g cartridge, eluting with a gradient of DCM to 30% MeOH in DCM) to give the product (300 mg) as a white solid.
¹ H NMR (D ₂ O): δ 9.66 (s, 1H), 9.27 (d, 1H), 9.04 (d, 1H), 8.28 (t, 1H), 7.75 (m, 4H), 6.25 (d, 1H ), 4.52 (t, 1H), 4.46 (m, 1H), 4.34 (apparent t, 1H), 4.03 (dd, 1H), 3.95 (ab q, 2H). MS(ESI+) m/z = 399.1

[Example 15]
compound 15
4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamido)benzoic acid.

無水ジオキサン(40mL)中の4-(ニコチンアミド)安息香酸(3.76g、9.59mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(3.20g、10.07mmol)の混合物に、トリエチルアミン(4.02mL、28.8mmol、3当量)を添加し、混合物を室温で15分間撹拌した。TMS-トリフレート(6.94mL、38.4mmol、3当量)を5分間にわたり添加し、反応物を20分間撹拌し、その後HPLC分析により反応が完了したことが示された。混合物を40mLのMTBEで希釈し、溶液を300mLのMTBEに注ぎ込み、得られた油を沈降させた。溶媒をデカンテーションした後、油を80mL分量のMTBEで2回研和した。残渣をEtOAc(50mL)に溶解し、2×30mL分量の水で洗浄し、無水Na₂SO₄で乾燥した。溶媒の濾過及び蒸発により、5.5gの粗トリアセテート中間体を得た。2.23gのこの材料を、DCM中5%MeOHからDCM中30%MeOHの勾配で溶出する600gのシリカゲルでクロマトグラフィー処理して、精製されたトリアセテート(1.3g)を白色固体として得た。トリアセテート:¹H NMR (CD₃CN): δ 9.68 (br s, 1H), 9,48 (d, 1H), 9.14 (d, 1H), 9.09 (dd, 1H), 8.33 (dd, 1H), 8.10 (d, 2H), 7.92 (d, 2H), 6.45 (m, 1H), 5.53 (d, 1H), 5.43 (t, 1H), 4.81 (q, 1H), 4.53 (dd, 1H), 4.50 (dd, 1H), 2.19 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H).

To a mixture of 4-(nicotinamido)benzoic acid (3.76 g, 9.59 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (3.20 g, 10.07 mmol) in anhydrous dioxane (40 mL) , triethylamine (4.02 mL, 28.8 mmol, 3 eq) was added and the mixture was stirred at room temperature for 15 min. TMS-triflate (6.94 mL, 38.4 mmol, 3 eq) was added over 5 minutes and the reaction was stirred for 20 minutes after which HPLC analysis indicated the reaction was complete. The mixture was diluted with 40 mL MTBE, the solution was poured into 300 mL MTBE and the resulting oil was allowed to settle. After decanting the solvent, the oil was triturated with two 80 mL portions of MTBE. The residue was dissolved in EtOAc (50 mL), washed with 2×30 mL portions of water, and dried over anhydrous Na ₂ SO ₄ . Filtration and evaporation of the solvent gave 5.5 g of crude triacetate intermediate. 2.23 g of this material was chromatographed on 600 g of silica gel eluting with a gradient of 5% MeOH in DCM to 30% MeOH in DCM to give the purified triacetate (1.3 g) as a white solid. Triacetate: ¹ H NMR (CD ₃ CN): δ 9.68 (br s, 1H), 9,48 (d, 1H), 9.14 (d, 1H), 9.09 (dd, 1H), 8.33 (dd, 1H), 8.10 (d, 2H), 7.92 (d, 2H), 6.45 (m, 1H), 5.53 (d, 1H), 5.43 (t, 1H), 4.81 (q, 1H), 4.53 (dd, 1H), 4.50 (dd, 1H), 2.19 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H).

Triacetate (1.3 g, 2.0 mmol) was dissolved in 4 mL of anhydrous MeOH and added under Ar to a well-stirred ice-cold solution of 1N NaOMe (6 mL, 6.0 mmol, 3 eq) in MeOH. The mixture was stirred for 20 minutes, then a cold solution of 1N HCl (6 mL, 6.0 mmol, 3 eq) in MeOH was added all at once. The color of the solution changed from dark orange to yellow and a solid precipitated out of solution (solution pH was 2). The product was filtered, washed thoroughly with MTBE, then dried under high vacuum to give the product (369 mg, 49%) as a pale pink solid.
1H NMR ₍ ^D2O ): δ 9.65 (s, 1H), 9.27 (d, 1H), 9.03 (d, 1H), 8.28 (t, 1H), 8.01 (q, 2H), 7.71 (br d, 2H), 6.25 (d, 1H), 4.52 (t, 1H), 4.47 (q, 1H), 4.35 (t, 1H), 4.03 (dd, 1H), 3.88 (dd, 1H). MS(ESI+) m /z = 375.1

[Example 16]
Compound 16
Methyl 2-chloro-4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamide)benzoate .

一般手順Bに従う:TMS-トリフレート(1.2当量)を、DCM(40mL)中のメチル2-クロロ-4-(ニコチンアミド)ベンゾエート(610mg、2.31mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。2時間撹拌した後、20mLの無水CH₃CNを添加して透明溶液を得、反応混合物を周囲温度でさらに1時間撹拌した。溶媒を減圧下で除去し、残渣をMeOHに溶解し、冷却し、MeOH中のSOCl₂(3当量)で処理した。混合物を16時間撹拌し、前述の通りの後処理により粗生成物を得、これをISCOで精製して白色固体(600mg、26%)を得た。
¹H NMR (D₂O): δ 9.64 (s, 1H), 9.28 (d, 1H), 9.03 (d, 1H), 8.29 (見かけ上t, 1H), 7.87 (d, 1H), 7.82 (d, 1H), 7.57 (dd, 1H), 6.24 (d, 1H), 4.52 (見かけ上t, 1H), 4.46 (m, 1H), 4.34 (見かけ上t, 1H), 4.03 (見かけ上dd, 1H), 3.95 (ab q, 2H). MS(ESI+) m/z = 423.1

Following General Procedure B: TMS-triflate (1.2 eq.) was combined with methyl 2-chloro-4-(nicotinamido)benzoate (610 mg, 2.31 mmol) and 1,2,3,5-tetraacetyl in DCM (40 mL). -β-D-ribofuranose (1.1 eq.) was added to the stirred mixture. After stirring for 2 hours, 20 mL of anhydrous CH ₃ CN was added to obtain a clear solution and the reaction mixture was stirred at ambient temperature for another hour. The solvent was removed under reduced pressure and the residue was dissolved in MeOH, cooled and treated with SOCl ₂ (3 eq) in MeOH. The mixture was stirred for 16 hours and workup as before gave the crude product, which was purified by ISCO to give a white solid (600mg, 26%).
¹ H NMR (D ₂ O): δ 9.64 (s, 1H), 9.28 (d, 1H), 9.03 (d, 1H), 8.29 (apparent t, 1H), 7.87 (d, 1H), 7.82 (d , 1H), 7.57 (dd, 1H), 6.24 (d, 1H), 4.52 (apparent t, 1H), 4.46 (m, 1H), 4.34 (apparent t, 1H), 4.03 (apparent dd, 1H ), 3.95 (ab q, 2H). MS(ESI+) m/z = 423.1

[Example 17]
compound 17
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(oxazol-2-yl)phenyl)-1λ ⁴ - Pyridine-3-carboxamide.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、無水アセトニトリル(40mL)中のN-(4-(オキサゾール-2-イル)フェニル)ニコチンアミド(900mg、3.4mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.2g、3.73mmol、1.1当量)の2時間の撹拌混合物に添加した。減圧下で溶媒を除去した後、残渣をMeOHに溶解し、3当量のSOCl₂で処理し、5℃で16時間撹拌した。前述の通りのその後の後処理により、粗生成物を淡褐色固体として得た。ISCO(40gのカートリッジ、DCMからDCM中30%MeOHの勾配溶出)での精製により、生成物を白色固体(650mg、48%)として得た。
¹H NMR (D₂O ): δ 11.74 (br s, 1H), 9.81(br s, 1H), 9.46 (d, 1H), 9.26 (d, 1H), 8.40 (t, 1H), 8.23 (d, 1H), 8.03-8.12 (m, 5H), 7.37 (br s, 1H), 6.25 (d, 1H), 4.43 (t, 1H), 4.28 (m, 1H), 4.20 (t, 1H), 3.79 (ab q, 2H). MS(ESI+) m/z = 398.1

According to general procedure B: TMS-triflate (1.2 eq.) was treated with N-(4-(oxazol-2-yl)phenyl)nicotinamide (900 mg, 3.4 mmol) and 1,2,3 in anhydrous acetonitrile (40 mL). ,5-Tetraacetyl-β-D-ribofuranose (1.2 g, 3.73 mmol, 1.1 eq) was added to the stirred mixture over 2 hours. After removal of solvent under reduced pressure, the residue was dissolved in MeOH, treated with 3 equivalents of SOCl ₂ and stirred at 5° C. for 16 hours. Subsequent workup as previously described gave the crude product as a light brown solid. Purification by ISCO (40 g cartridge, gradient elution from DCM to 30% MeOH in DCM) gave the product as a white solid (650 mg, 48%).
¹ H NMR (D ₂ O ): δ 11.74 (br s, 1H), 9.81 (br s, 1H), 9.46 (d, 1H), 9.26 (d, 1H), 8.40 (t, 1H), 8.23 (d , 1H), 8.03-8.12 (m, 5H), 7.37 (br s, 1H), 6.25 (d, 1H), 4.43 (t, 1H), 4.28 (m, 1H), 4.20 (t, 1H), 3.79 (ab q, 2H). MS(ESI+) m/z = 398.1

[Example 18]
Compound 18
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(2-methyl-1,3-dioxoisoindoline-5- yl)-1λ ⁴ -pyridine-3-carboxamide.

一般手順Bに従う:TMS-トリフレート(1.91mL、10.34mmol、1.2当量)を、CH₃CN(80mL)中のN-(2-メチル-1,3-ジオキソイソインドリン-5-イル)ニコチンアミド(2.46g、8.75mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(3.04g、9.56mmol、1.1当量)の撹拌混合物に添加した。周囲温度で3時間撹拌し、続いて溶媒を除去してMeOH中のSOCl₂(3当量)で処理し、16時間撹拌した後、MTBEで研和すると粗生成物を淡褐色固体として得た。精製をISCO(40gのカートリッジ、DCMからDCM中30%MeOHの勾配での溶出)で達成した。純粋な画分を合わせ、減圧下で溶媒を蒸発させた後、生成物(1.05g、29%)をオフホワイトの固体として得た。
¹H NMR (D₂O ): δ 9.69 (s, 1H), 9.31 (d, 1H), 9.07 (d, 1H), 8.34 (t, 1H), 8.08 (s, 1H), 7.83 (dd, 2H), 6.26 (d, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 4.36 (t, 1H), 3.95 (ab q, 2H), 3.07 (s, 3H). MS(ESI+) m/z = 414.1

According to general procedure B: TMS-triflate (1.91 mL, 10.34 mmol, 1.2 equiv) to N-(2-methyl-1,3-dioxoisoindolin-5-yl)nicotine in _CH3CN (80 mL) Added to a stirred mixture of amide (2.46 g, 8.75 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (3.04 g, 9.56 mmol, 1.1 eq). Stirring at ambient temperature for 3 hours followed by removal of solvent and treatment with SOCl ₂ (3 eq) in MeOH, stirring for 16 hours followed by trituration with MTBE gave the crude product as a pale brown solid. Purification was achieved by ISCO (40g cartridge, elution with a gradient of DCM to 30% MeOH in DCM). After combining the pure fractions and evaporating the solvent under reduced pressure, the product (1.05 g, 29%) was obtained as an off-white solid.
¹ H NMR (D ₂ O ): δ 9.69 (s, 1H), 9.31 (d, 1H), 9.07 (d, 1H), 8.34 (t, 1H), 8.08 (s, 1H), 7.83 (dd, 2H ), 6.26 (d, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 4.36 (t, 1H), 3.95 (ab q, 2H), 3.07 (s, 3H). MS(ESI+) m /z = 414.1

[Example 19]
compound 19
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(2-methyl-3-oxoisoindolin-5-yl)- 1λ ⁴ -pyridine-3-carboxamide.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、無水CH₃CN(50mL)中のN-(2-メチル-3-オキソイソインドリン-5-イル)ニコチンアミド(1.25g、4.7mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で3時間撹拌し、続いて溶媒を蒸発させてMeOH中のSOCl₂(3当量)で5℃で24時間処理した後、研和すると粗生成物をオフホワイトの固体として得た。ISCO(40gのカートリッジ、DCMからDCM中40%MeOHの勾配で溶出)で精製して、純粋な生成物(650mg、35%)を白色固体として得た。
¹H NMR (D₂O): δ 9.65 (s, 1H), 9.28 (d, 1H), 9.04 (d, 1H), 8.30 (t, 1H), 7.83 (s, 1H), 7.83 (s, 1H), 7.66 (d, 1H), 7.57 (d, 1H), 6.26 (d, 1H), 5.42 (s, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 3.95 (ab q, 2H), 3.10 (s, 1H). MS(ESI+) m/z = 400.2

Following General Procedure B: TMS-triflate (1.2 eq.) was treated with N-(2-methyl-3-oxoisoindolin-5-yl)nicotinamide (1.25 g, 4.7 mmol) in anhydrous _CH3CN (50 mL). and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq) was added to a stirred mixture. Stirring at ambient temperature for 3 hours followed by evaporation of the solvent and treatment with SOCl ₂ (3 eq) in MeOH at 5° C. for 24 hours followed by trituration gave the crude product as an off-white solid. Purification by ISCO (40 g cartridge, eluting with a gradient of DCM to 40% MeOH in DCM) gave pure product (650 mg, 35%) as a white solid.
¹ H NMR (D ₂ O): δ 9.65 (s, 1H), 9.28 (d, 1H), 9.04 (d, 1H), 8.30 (t, 1H), 7.83 (s, 1H), 7.83 (s, 1H ), 7.66 (d, 1H), 7.57 (d, 1H), 6.26 (d, 1H), 5.42 (s, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 3.95 (ab q, 2H ), 3.10 (s, 1H). MS(ESI+) m/z = 400.2

[Example 20]
Compound 20
N-(3-Carbamoylphenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamide.

TMS-トリフレート(1.3mL、7.1mmol、1.2当量)を、CH₃CN(60mL)中のN-(3-カルバモイルフェニル)ニコチンアミド(1.42g、6.75mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(2.2g、6.8mmol、1.1当量)の撹拌混合物に室温で添加した。2時間撹拌した後、溶媒を除去し、残渣を酢酸エチルに吸収させた。溶液を分液漏斗に移し、5% NaHCO₃水溶液、水及びブラインで連続的に洗浄し、次いで無水Na₂SO₄で乾燥した。溶液を濾過及び濃縮し、DCMからDCM中20%MeOHで溶出するISCO(40gのカートリッジ)で残渣を精製した。生成物を含有する画分をプールし、濃縮して、トリアセテート中間体(405mg)を泡として得た。この材料を無水MeOH(20mL)に溶解し、氷浴中で冷却し、3当量のSOCl₂で処理した。溶液を5℃で24時間撹拌した。溶液をMTBEで研和して、生成物を白色固体として沈殿させ、これを濾過により収集した。生成物を吸引漏斗でいくつかの分量のMTBEで洗浄し、次いで高真空下に置いて微量のHClを除去した。生成物(140mg、6%)を白色固体として得た。
¹H NMR (D₂O): δ 9.68 (s, 1H), 9.28 (d, 1H), 9.05 (d, 1H), 8.29 (t, 1H), 7.97 (s, 1H), 7.76 (d, 1H), 7.68 (d, 1H), 7.56 (t, 1H), 6.25 (d, 1H), 4.51 (見かけ上t, 1H), 4.47 (m, 1H), 4.36 (t, 1H), 3.95 (ab q, 2H). MS(ESI+) m/z = 374.1

TMS-triflate (1.3 mL, 7.1 mmol, 1.2 eq) was treated with N-( ₃ -carbamoylphenyl)nicotinamide (1.42 g, 6.75 mmol) and 1,2,3,5- Added to a stirred mixture of tetraacetyl-β-D-ribofuranose (2.2 g, 6.8 mmol, 1.1 eq) at room temperature. After stirring for 2 hours the solvent was removed and the residue was taken up in ethyl acetate. The solution was transferred to a separatory funnel and washed successively with ₅ % aqueous _NaHCO3 , water and brine, then dried over anhydrous _Na2SO4 . The solution was filtered and concentrated and the residue purified by ISCO (40 g cartridge) eluting with DCM to 20% MeOH in DCM. Fractions containing product were pooled and concentrated to give the triacetate intermediate (405 mg) as a foam. This material was dissolved in anhydrous MeOH (20 mL), cooled in an ice bath, and treated with 3 equivalents of SOCl ₂ . The solution was stirred at 5°C for 24 hours. The solution was triturated with MTBE to precipitate the product as a white solid, which was collected by filtration. The product was washed with several aliquots of MTBE on a suction funnel and then placed under high vacuum to remove traces of HCl. The product (140mg, 6%) was obtained as a white solid.
¹ H NMR (D ₂ O): δ 9.68 (s, 1H), 9.28 (d, 1H), 9.05 (d, 1H), 8.29 (t, 1H), 7.97 (s, 1H), 7.76 (d, 1H ), 7.68 (d, 1H), 7.56 (t, 1H), 6.25 (d, 1H), 4.51 (apparent t, 1H), 4.47 (m, 1H), 4.36 (t, 1H), 3.95 (ab q , 2H). MS(ESI+) m/z = 374.1

[Example 21]
Compound 21
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(3-oxo-1,3-dihydroisobenzofuran-5-yl )-1λ ⁴ -pyridine-3-carboxamide.

一般手順Bに従う:TMS-トリフレート(0.75mL、4.1mmol、1.2当量)を、CH₃CN(25mL)中のN-(3-オキソ-1,3-ジヒドロイソベンゾフラン-5-イル)ニコチンアミド(0.85g、3.4mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.2g、3.7mmol、1.1当量)の撹拌混合物に添加した。周囲温度で1.5時間撹拌し、続いて溶媒を除去してMeOH中のSOCl₂(3.5当量)で処理した後、溶液を5℃で24時間撹拌した。溶液にMTBEを徐々に添加して粗生成物を沈殿させ、これをMTBEで研和し、残渣をDCMと、続いてCH₃CNと同時ストリッピングして、微量のHClを除去した。残渣をDCM中最低20%のMeOHに溶解し、24gのISCOカートリッジに投入した。DCM中5%から30%のMeOHで溶出し、続いて純粋な画分を蒸発させて、純粋な生成物(505mg、38%)を得た。
¹H NMR (D₂O): δ 9.68 (s, 1H), 9.28 (d, 1H), 9.06 (d, 1H), 8.32 (t, 1H), 8.12 (s, 1H), 7.89 (d, 1H), 7.66 (d, 1H), 6.26 (d, 1H), 5.43 (s, 2H), 4.54 (t, 1H), 4.46 (m, 1H), 4.36 (t, 1H). MS(ESI+) m/z = 387.1

According to general procedure B: TMS-triflate (0.75 mL, 4.1 mmol, 1.2 equiv) to N-(3-oxo-1,3-dihydroisobenzofuran-5-yl)nicotinamide in _CH3CN (25 mL). (0.85 g, 3.4 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.2 g, 3.7 mmol, 1.1 eq) was added to a stirred mixture. After stirring at ambient temperature for 1.5 hours followed by removal of solvent and treatment with SOCl ₂ (3.5 eq) in MeOH, the solution was stirred at 5° C. for 24 hours. Slow addition of MTBE to the solution precipitated the crude product, which was triturated with MTBE and the residue was co-stripped with DCM followed by CH ₃ CN to remove traces of HCl. The residue was dissolved in minimum 20% MeOH in DCM and loaded onto a 24g ISCO cartridge. Elution with 5% to 30% MeOH in DCM followed by evaporation of pure fractions gave pure product (505mg, 38%).
¹ H NMR (D ₂ O): δ 9.68 (s, 1H), 9.28 (d, 1H), 9.06 (d, 1H), 8.32 (t, 1H), 8.12 (s, 1H), 7.89 (d, 1H ), 7.66 (d, 1H), 6.26 (d, 1H), 5.43 (s, 2H), 4.54 (t, 1H), 4.46 (m, 1H), 4.36 (t, 1H). MS(ESI+) m/ z = 387.1

[Example 22]
Compound 22
Methyl 1-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carbonyl)indoline-5-carboxy rate.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、CH₃CN(16mL)中のメチル1-ニコチノイルインドリン-5-カルボキシレート(0.5g、1.78mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で2時間撹拌した後、溶媒を除去し、残渣をMeOHに溶解し、冷却し、SOCl₂(3当量)で処理した。5℃で16時間撹拌した後、MTBEで研和すると粗生成物をオフホワイトの固体として得た。精製をISCO(40gのカートリッジ、DCM中10%MeOHからDCM中30%MeOHの勾配での溶出)で標準の様式で達成して、生成物(330mg、45%)をオフホワイトの固体として得た。
¹H NMR (D₂O): δ 9.45 (br s, 1H), 9.25 (d, 1H), 8.85 (d, 1H), 8.3 (t, 1H), 7.70-8.10 (m, 3H), 6.23 (br s, 1H), 4.47 (m, 2H), 4.35 (m, 1H), 3.92 -4.20 (m, 3H), 3.85 (s, 3H), 3.16 (m, 2H). MS(ESI+) m/z = 415.2

According to general procedure B: TMS-triflate (1.2 eq) was combined with methyl 1-nicotinoylindoline-5-carboxylate (0.5 g, 1.78 mmol) and _1,2,3,5- Added to a stirred mixture of tetraacetyl-β-D-ribofuranose (1.1 eq). After stirring for 2 hours at ambient temperature the solvent was removed and the residue was dissolved in MeOH, cooled and treated with SOCl ₂ (3 eq). After stirring for 16 h at 5° C., trituration with MTBE gave the crude product as an off-white solid. Purification was accomplished in standard fashion on an ISCO (40g cartridge, elution with a gradient of 10% MeOH in DCM to 30% MeOH in DCM) to give the product (330 mg, 45%) as an off-white solid. .
¹ H NMR (D ₂ O): δ 9.45 (br s, 1H), 9.25 (d, 1H), 8.85 (d, 1H), 8.3 (t, 1H), 7.70-8.10 (m, 3H), 6.23 ( br s, 1H), 4.47 (m, 2H), 4.35 (m, 1H), 3.92 -4.20 (m, 3H), 3.85 (s, 3H), 3.16 (m, 2H). MS(ESI+) m/z = 415.2

[Example 23]
Compound 23
Methyl (4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-carboxamido)benzoyl)glycinate.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、CH₃CN(15mL)中のメチル(4-(ニコチンアミド)ベンゾイル)グリシネート(0.5g、1.6mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で2時間撹拌し、溶媒を除去してMeOH中のSOCl₂(3.5当量)で処理した後、溶液を5℃で16時間撹拌した。その時点でのHPLCでは10%のモノ-アセテートの残留が示されたため、追加のSOCl₂(0.1mL)を添加し、撹拌を6時間継続した。MTBEで研和した後、粗生成物をオフホワイトの固体として得た。ISCO(12gのカートリッジ、DCM中5%MeOHからDCM中30%MeOHの勾配での溶出)での精製により、生成物(155mg、22%)をオフホワイトの固体として得た。
¹H NMR (D₂O): δ 9.65 (br s, 1H), 9.26 (d, 1H), 9.03 (m, 1H), 8.27 (t, 1H), 7.65-7.88 (m, 4H), 6.24 (d, 1H), 4.50 (t, 1H), 4.45 (t, 1H), 4.35 (m, 1H), 4.15 (br s, 1H), 3.95 (ab q), 3.75 (s, 3H). MS(ESI+) m/z = 446.2

According to general procedure B: TMS-triflate (1.2 eq) was treated with methyl (4-(nicotinamido)benzoyl)glycinate (0.5 g, 1.6 mmol) and _1,2,3,5- Added to a stirred mixture of tetraacetyl-β-D-ribofuranose (1.1 eq). After stirring at ambient temperature for 2 hours, solvent removal and treatment with SOCl ₂ (3.5 eq) in MeOH, the solution was stirred at 5° C. for 16 hours. HPLC at that time indicated 10% mono-acetate remaining, so additional SOCl ₂ (0.1 mL) was added and stirring continued for 6 h. The crude product was obtained as an off-white solid after trituration with MTBE. Purification by ISCO (12 g cartridge, elution with a gradient of 5% MeOH in DCM to 30% MeOH in DCM) gave the product (155 mg, 22%) as an off-white solid.
¹ H NMR (D ₂ O): δ 9.65 (br s, 1H), 9.26 (d, 1H), 9.03 (m, 1H), 8.27 (t, 1H), 7.65-7.88 (m, 4H), 6.24 ( d, 1H), 4.50 (t, 1H), 4.45 (t, 1H), 4.35 (m, 1H), 4.15 (br s, 1H), 3.95 (ab q), 3.75 (s, 3H). ) m/z = 446.2

[Example 24]
Compound 24
Ethyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamido)benzoate.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、CH₃CN(20mL)中のエチル4-(ニコチンアミド)ベンゾエート(0.5g、1.85mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で3時間撹拌した後、溶媒を蒸発させ、残渣を無水EtOH(20mL)に吸収させ、氷浴中で冷却した。SOCl₂(3.5当量)を滴下により添加し、溶液を5℃で72時間静置した。前述の通りの後処理により、粗生成物を半固体物質として得た。粗生成物を、15分間にわたりDCM中5～30%MeOHの勾配で溶出するISCO(24gのカートリッジ、DCM中10%MeOHを添加)で精製した。純粋な画分をプールし、ストリッピングし、微量の溶媒を高真空下で除去した。生成物(145mg、19%)をオフホワイトの固体として得た。
¹H NMR (DMSOd₆): δ 11.75 (s, 1H), 9.79 (s, 1H), 9.46 (d, 1H), 8.38 (t, 1H), 8.04 (m, 4H), 6.24 (d, 1H), 4.42 (t, 1H), 4.22-4.35 (m, 3H), 4.18 (t, 1H), 3.80 (ab q, 2H), 1.33 (t, 3H). MS(ESI+) m/z = 403.2

According to general procedure B: TMS-triflate (1.2 eq.) was treated with ethyl 4-(nicotinamido)benzoate (0.5 g, 1.85 mmol) and 1,2,3,5-tetraacetyl- in _CH3CN (20 mL). Added to a stirred mixture of β-D-ribofuranose (1.1 eq). After stirring for 3 hours at ambient temperature the solvent was evaporated and the residue was taken up in absolute EtOH (20 mL) and cooled in an ice bath. SOCl ₂ (3.5 eq) was added dropwise and the solution was allowed to stand at 5° C. for 72 hours. Workup as previously described gave the crude product as a semi-solid material. The crude product was purified by ISCO (24g cartridge, adding 10% MeOH in DCM) eluting with a gradient of 5-30% MeOH in DCM over 15 minutes. Pure fractions were pooled, stripped and traces of solvent removed under high vacuum. The product (145 mg, 19%) was obtained as an off-white solid.
¹ H NMR (DMSOd ₆ ): δ 11.75 (s, 1H), 9.79 (s, 1H), 9.46 (d, 1H), 8.38 (t, 1H), 8.04 (m, 4H), 6.24 (d, 1H). , 4.42 (t, 1H), 4.22-4.35 (m, 3H), 4.18 (t, 1H), 3.80 (ab q, 2H), 1.33 (t, 3H). MS(ESI+) m/z = 403.2

[Example 25]
Compound 25
Methyl 5-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamido)picolinate.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、CH₃CN(50mL)中のメチル5-(ニコチンアミド)ピコリネート(1.21g、4.8mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で3時間撹拌した後、溶媒を蒸発させ、残渣を無水MeOH(40mL)に吸収させ、氷浴中で冷却し、SOCl₂(3.5当量)で処理した。5℃で24時間撹拌した後、溶液を10mLまで濃縮し、生成物をMTBEで沈殿させた。生成物を焼結ガラス漏斗を通して濾過し、2×5mL分量の氷冷MeOHで、次いで過剰のMTBEで連続的に洗浄した。高真空下で微量の溶媒を除去した後、生成物(650mg、35%)が白色固体として単離された。
¹H NMR (D₂O): δ 9.63 (s, 1H), 9.26 (d, 1H), 9.03 (d, 1H), 8.26 (見かけ上t, 1H), 7.84 (br s, 1H), 7.70 (m, 1H), 7.59 (m, 1H), 6.23 (d, 1H), 4.47 (t, 1H), 4.42 (s, 3H), 4.33 (見かけ上t, 1H), 3.94 (ab q, 2H). MS(ESI+) m/z = 390.1

According to general procedure B: TMS-triflate (1.2 eq) was treated with methyl 5-(nicotinamido)picolinate (1.21 g _, 4.8 mmol) and 1,2,3,5-tetraacetyl- Added to a stirred mixture of β-D-ribofuranose (1.1 eq). After stirring for 3 hours at ambient temperature the solvent was evaporated and the residue was taken up in anhydrous MeOH (40 mL), cooled in an ice bath and treated with SOCl ₂ (3.5 eq). After stirring for 24 hours at 5° C., the solution was concentrated to 10 mL and the product was precipitated with MTBE. The product was filtered through a sintered glass funnel and washed successively with 2 x 5 mL aliquots of ice-cold MeOH and then excess MTBE. The product (650 mg, 35%) was isolated as a white solid after removing traces of solvent under high vacuum.
¹ H NMR (D ₂ O): δ 9.63 (s, 1H), 9.26 (d, 1H), 9.03 (d, 1H), 8.26 (apparent t, 1H), 7.84 (br s, 1H), 7.70 ( m, 1H), 7.59 (m, 1H), 6.23 (d, 1H), 4.47 (t, 1H), 4.42 (s, 3H), 4.33 (apparent t, 1H), 3.94 (ab q, 2H). MS(ESI+) m/z = 390.1

[Example 26]
Compound 26
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(1-oxoisoindolin-5-yl)-1λ ⁴ -pyridine -3-carboxamide.

一般手順Aに従う:TMS-トリフレート(1.2当量)を、CH₃CN(20mL)中のN-(1-オキソイソインドリン-5-イル)ニコチンアミド(0.56g、2.2mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で1.5時間撹拌した後、溶媒を蒸発させ、残渣を無水MeOH(20mL)に吸収させ、氷浴中で冷却した。SOCl₂(3.5当量)を滴下により添加し、溶液を5℃で18時間撹拌した。生成物をMTBEで沈殿させ、溶媒をデカンテーションし、固体をMeOHに再溶解し、MTBEで沈殿させた。MTBEで研和した後、固体(吸湿性)をCH₃CNと共蒸発させて、微量の水及びHClを除去した。純粋な生成物(600mg、71%)をオフホワイトの固体として得た。
¹H NMR (DMSO-d₆): δ 11.9 (br s, 1H), 9.81 (d, 1H), 9.27 (見かけ上d, 1H), 9.16 (見かけ上d, 1H), 8.48 (m, 1H), 8.43 (見かけ上t, 1H), 8.18 (d, 1H), 6.24 (d, 1H), 4.40 (見かけ上t, 1H), 4.29 (m, 1H), 4.19 (見かけ上t, 1H), 3.87 (s, 2H), 3.81 (ab q, 2H). MS(ESI+) m/z = 386.1

According to general procedure A: TMS-triflate (1.2 eq) was treated with N-(1-oxoisoindolin-5-yl)nicotinamide (0.56 g, 2.2 mmol) and 1,2, in _CH3CN (20 mL). Added to a stirred mixture of 3,5-tetraacetyl-β-D-ribofuranose (1.1 eq). After stirring for 1.5 hours at ambient temperature the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL) and cooled in an ice bath. SOCl ₂ (3.5 eq) was added dropwise and the solution was stirred at 5° C. for 18 hours. The product was precipitated with MTBE, the solvent was decanted, the solid was redissolved in MeOH and precipitated with MTBE. After trituration with MTBE, the solid (hygroscopic) was co-evaporated with CH ₃ CN to remove traces of water and HCl. Pure product (600 mg, 71%) was obtained as an off-white solid.
¹ H NMR (DMSO-d ₆ ): δ 11.9 (br s, 1H), 9.81 (d, 1H), 9.27 (apparent d, 1H), 9.16 (apparent d, 1H), 8.48 (m, 1H). , 8.43 (apparent t, 1H), 8.18 (d, 1H), 6.24 (d, 1H), 4.40 (apparent t, 1H), 4.29 (m, 1H), 4.19 (apparent t, 1H), 3.87 (s, 2H), 3.81 (ab q, 2H). MS(ESI+) m/z = 386.1

[Example 27]
compound 27
2-(dimethylamino)ethyl 4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamide ) benzoate.

TMS-トリフレート(3.0g、13.7mmol)を、40mLのDCM中の2-(ジメチルアミノ)エチル4-(ニコチンアミド)ベンゾエート(1.8g、5.7mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.8g、5.7mmol)の撹拌溶液に、氷浴中で5分間にわたり添加した。反応混合物を周囲温度まで温め、一晩撹拌した。溶媒をストリッピングし、残渣をEtOAcに溶解した。これを水、飽和NaHCO₃及びブラインで洗浄し、次いでNa₂SO₄で乾燥し、真空下で蒸発乾固して、2.5gのトリアセテートを固体として得た。この化合物を25mLの無水MeOHに溶解し、氷浴中で冷却した後、1.63g(20.8mmol、3.65当量)の塩化アセチルで滴下により処理した。混合物をアルゴン下に置き、10℃で一晩静置し、次いで周囲温度まで温め、3時間撹拌した。溶媒をほぼ乾燥するまでストリッピングし、残渣をヘキサン(2×150mL)で、続いてMTBE(3×100mL)で研和した。残渣をMeOH(10mL)に吸収させ、高真空下で蒸発させて、2.1gの固体を得た。固体を250mLのアセトンに懸濁させ、5% NaHCO₃水溶液で中性となるまで処理した。冷凍庫内で数時間静置した後、混合物を濾過し、濾液を蒸発させて油状とし、冷凍及び凍結乾燥させて、生成物(650mg、43%)を褐色固体として得た。
¹H NMR (D₂O/CD₃CN): δ 10.0 (s, 1H), 9.6 (s, 1H), 9.4 (dd, 1H), 8.7 (s, 1H), 8.5 (d, 2H), 8.2 (d, 2H), 6.5 (d, 1H), 4.75 (m, 4H), 4.3 (m, 1H), 4.2 (m, 1H), 3.4 (m, 2H), 2.9 (s, 6H). MS(ESI+) m/z= 446.2

TMS-triflate (3.0 g, 13.7 mmol) was treated with 2-(dimethylamino)ethyl 4-(nicotinamido)benzoate (1.8 g, 5.7 mmol) and 1,2,3,5-tetraacetyl in 40 mL of DCM. -β-D-ribofuranose (1.8 g, 5.7 mmol) was added to a stirred solution over 5 minutes in an ice bath. The reaction mixture was warmed to ambient temperature and stirred overnight. Solvent was stripped and the residue was dissolved in EtOAc. This was washed with water, saturated NaHCO ₃ and brine, then dried over Na ₂ SO ₄ and evaporated to dryness under vacuum to give 2.5 g of triacetate as a solid. This compound was dissolved in 25 mL of anhydrous MeOH, cooled in an ice bath and then treated dropwise with 1.63 g (20.8 mmol, 3.65 eq) of acetyl chloride. The mixture was placed under argon and left at 10° C. overnight, then warmed to ambient temperature and stirred for 3 hours. The solvent was stripped to near dryness and the residue was triturated with hexanes (2 x 150 mL) followed by MTBE (3 x 100 mL). The residue was taken up in MeOH (10 mL) and evaporated under high vacuum to give 2.1 g of solid. The solid was suspended in 250 mL of acetone and treated with 5% NaHCO ₃ aqueous solution until neutral. After standing in the freezer for several hours, the mixture was filtered and the filtrate was evaporated to an oil, frozen and lyophilized to give the product (650mg, 43%) as a brown solid.
< ¹ >H NMR ₍ D2O/ _CD3CN ): [delta] 10.0 (s, 1H), 9.6 (s, 1H), 9.4 (dd, 1H), 8.7 (s, 1H), 8.5 (d, 2H), 8.2 (d, 2H), 6.5 (d, 1H), 4.75 (m, 4H), 4.3 (m, 1H), 4.2 (m, 1H), 3.4 (m, 2H), 2.9 (s, 6H). ESI+) m/z= 446.2

[Example 28]
Compound 28
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(N,N-dimethylsulfamoyl)phenyl)- 1λ ⁴ -pyridine-3-carboxamide.

一般手順Aに従う:TMS-トリフレート(1.2当量)を、CH₃CN(20mL)中のN-(4-(N,N-ジメチルスルファモイル)フェニル)ニコチンアミド(0.55g、1.8mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で2時間撹拌した後、溶媒を蒸発させ、残渣を無水MeOH(20mL)に吸収させ、氷浴中で冷却した。SOCl₂(3.5当量)を滴下により添加し、溶液を冷凍庫内で-5℃で72時間静置した。溶液を室温にし、生成物をMTBEで沈殿させた。生成物から溶媒をデカンテーションし、固体を5mLのMeOHに溶解し、周囲温度で1時間撹拌した。微細な白色沈殿物が形成し、これを焼結ガラス漏斗で濾過し、氷冷MeOH(5mL)で、続いてMTBEで洗浄した。純粋な生成物(220mg、28%)をオフホワイトの固体として得た。
¹H NMR (D₂O): δ 9.68 (br s, 1H), 9.28 (d, 1H), 9.05 (d, 1H), 8.29 (t, 1H), 7.83 (m, 4H), 6.25, (d, 1H), 4.43-4.57 (m, 2H), 4.36 (t, 1H), 3.95 (ab q, 2H), 2.65 (s, 6H). MS(ESI+) m/z= 438.1

According to general procedure A: TMS-triflate (1.2 eq) was treated with N-(4-(N,N-dimethylsulfamoyl)phenyl)nicotinamide (0.55 g, 1.8 mmol) in _CH3CN (20 mL) and Added to a stirred mixture of 1,2,3,5-tetraacetyl-β-D-ribofuranose (1.1 eq). After stirring for 2 hours at ambient temperature the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL) and cooled in an ice bath. SOCl ₂ (3.5 eq) was added dropwise and the solution was placed in a freezer at −5° C. for 72 hours. The solution was brought to room temperature and the product was precipitated with MTBE. The solvent was decanted from the product and the solid was dissolved in 5 mL of MeOH and stirred at ambient temperature for 1 hour. A fine white precipitate formed which was filtered through a sintered glass funnel and washed with ice-cold MeOH (5 mL) followed by MTBE. Pure product (220 mg, 28%) was obtained as an off-white solid.
1H NMR ₍ ^D2O ): δ 9.68 (br s, 1H), 9.28 (d, 1H), 9.05 (d, 1H), 8.29 (t, 1H), 7.83 (m, 4H), 6.25, (d , 1H), 4.43-4.57 (m, 2H), 4.36 (t, 1H), 3.95 (ab q, 2H), 2.65 (s, 6H). MS(ESI+) m/z= 438.1

[Example 29]
Compound 29
Methyl 2-(4-(1-((2R,3R,4S,5R)-3,4-dihydroxy-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamido)phenyl)acetate.

一般手順Bに従う:TMS-トリフレート(1.2当量)を、DCM(20mL)中のメチル2-(4-(ニコチンアミド)フェニル)アセテート(0.50g、1.85mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。30分間撹拌した後、アリコートのHPLC分析では約20%のみの変換が示されたため、追加のTMS-トリフレート(1.2当量)を添加した。反応混合物を周囲温度で1.5時間撹拌し、溶媒を蒸発させ、残渣を無水MeOH(20mL)に吸収させた。SOCl₂(3.5当量)を0℃で溶液に滴下により添加し、反応混合物を5℃で16時間撹拌した。その時点でのHPLC分析では約25%のモノ及びジアセテート中間体の存在が示されたため、追加のSOCl₂(1当量)を添加し、撹拌をさらに5時間継続した。前述の通りの後処理、及び通常の様式でのISCOでの精製により、生成物(340mg、46%)を得た。
¹H NMR (D₂O): δ 9.65 (s, 1H), 9.26 (d, 1H), 9.04 (d, 1H), 8.27 (t, 1H), 7.45 (d, 2H), 7.35 (d, 2H), 6.24 (d, 1H), 4.52 (見かけ上t, 1H), 4.46 (m, 1H), 4.35 (t, 1H), 3.94 (ab q, 2H), 3.74 (s, 2H), 3.68 (s, 3H). MS(ESI+) m/z = 403.2

According to general procedure B: TMS-triflate (1.2 eq) is combined with methyl 2-(4-(nicotinamido)phenyl)acetate (0.50 g, 1.85 mmol) and 1,2,3,5- Added to a stirred mixture of tetraacetyl-β-D-ribofuranose (1.1 eq). After stirring for 30 minutes, HPLC analysis of an aliquot showed only about 20% conversion, so additional TMS-triflate (1.2 eq) was added. The reaction mixture was stirred at ambient temperature for 1.5 hours, the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL). SOCl ₂ (3.5 eq) was added dropwise to the solution at 0° C. and the reaction mixture was stirred at 5° C. for 16 hours. At that time HPLC analysis indicated the presence of ˜25% mono- and diacetate intermediates, so additional SOCl ₂ (1 eq) was added and stirring continued for a further 5 h. Workup as previously described and ISCO purification in the usual manner gave the product (340 mg, 46%).
¹ H NMR (D ₂ O): δ 9.65 (s, 1H), 9.26 (d, 1H), 9.04 (d, 1H), 8.27 (t, 1H), 7.45 (d, 2H), 7.35 (d, 2H ), 6.24 (d, 1H), 4.52 (apparent t, 1H), 4.46 (m, 1H), 4.35 (t, 1H), 3.94 (ab q, 2H), 3.74 (s, 2H), 3.68 (s , 3H). MS(ESI+) m/z = 403.2

[Example 30]
compound 30
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(4-(oxazol-5-yl)phenyl)-1λ ⁴ - Pyridine-3-carboxamide.

一般手順Aに従う:TMS-トリフレート(1.2当量)を、CH₃CN(40mL)中のN-(4-(オキサゾール-5-イル)フェニル)ニコチンアミド(1.1g、4.2mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で2時間撹拌した後、溶媒を蒸発させ、残渣を無水MeOH(20mL)に吸収させ、氷浴中で冷却した。塩化チオニル(3.5当量)で処理し、続いて5℃で一晩撹拌した後、生成物が溶液から沈殿した。固体を濾過により収集し、2×5mL分量の氷冷MeOHで、続いて大量のMTBEで洗浄した。固体を高真空下で数時間乾燥させて、0.54g(32%)の生成物を淡黄色固体として得た。
¹H NMR (DMSO-d₆): δ 9.56 (s, 1H), 9.23 (d, 1H), 8.94 (d, 1H), 8.22 (m, 2H), 7.62 (q, 4H), 7.39 (s, 1H), 6.19 (d, 1H), 4.46 (m, 2H), 4.34 (t, 1H), 3.94 (ab q, 2H). MS(ESI+) m/z = 398.1

According to general procedure A: TMS-triflate (1.2 eq) was treated with N-(4-(oxazol-5-yl)phenyl)nicotinamide (1.1 g, 4.2 mmol) and 1,2 in _CH3CN (40 mL). ,3,5-Tetraacetyl-β-D-ribofuranose (1.1 eq) was added to a stirred mixture. After stirring for 2 hours at ambient temperature the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL) and cooled in an ice bath. After treatment with thionyl chloride (3.5 eq) followed by stirring overnight at 5° C., the product precipitated out of solution. The solid was collected by filtration and washed with 2 x 5 mL portions of ice-cold MeOH followed by copious amounts of MTBE. The solid was dried under high vacuum for several hours to give 0.54 g (32%) of product as a pale yellow solid.
¹ H NMR (DMSO-d ₆ ): δ 9.56 (s, 1H), 9.23 (d, 1H), 8.94 (d, 1H), 8.22 (m, 2H), 7.62 (q, 4H), 7.39 (s, 1H), 6.19 (d, 1H), 4.46 (m, 2H), 4.34 (t, 1H), 3.94 (ab q, 2H). MS(ESI+) m/z = 398.1

[Example 31]
compound 31
Methyl 6-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1λ ⁴ -pyridine-3-carboxamido)nicotinate.

一般手順Aに従う:TMS-トリフレート(1.2当量)を、無水CH₃CN(20mL)中のメチル6-(ニコチンアミド)ニコチネート(0.50g、1.95mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加した。周囲温度で2時間撹拌した後、溶媒を蒸発させ、残渣を無水MeOH(20mL)に吸収させ、氷浴中で冷却した。混合物をSOCl₂(3.5当量)で処理し、5℃で16時間撹拌した。その時点でのHPLCではまだ約10%のモノ及びジ-アセテート中間体の混合物が示されたため、追加のSOCl₂(1当量)を添加し、撹拌を5時間継続した。生成物をMTBEの添加により沈殿させて白色固体を得、これをMTBEで数回研和した。粗生成物を10mLの無水MeOHに再溶解し、前述のようにMTBEで沈殿させた。生成物を濾過し、2×5mL分量の氷冷MeOHで、続いて大量のMTBEで洗浄した。高真空下で数時間乾燥させた後、生成物を白色固体(100mg、13%)として得た。
¹H NMR (D₂O): δ 9.72 (s, 1H), 9.28 (d, 1H), 9.08 (d, 1H), 8.93 (見かけ上d, 1H), 8.44 (dd, 1H), 8.32 (t, 1H), 8.10 (見かけ上d, 4H), 6.25 (d, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 4.34 (t, 1H), 3.95 (ab q, 2H), 3.92 (s, 3H). MS(ESI+) m/z = 390.1

According to General Procedure A: TMS-triflate (1.2 eq.) was treated with methyl 6-(nicotinamido)nicotinate (0.50 g, 1.95 mmol) and 1,2,3,5-tetraacetyl in anhydrous _CH3CN (20 mL). -β-D-ribofuranose (1.1 eq.) was added to the stirring mixture. After stirring for 2 hours at ambient temperature the solvent was evaporated and the residue was taken up in anhydrous MeOH (20 mL) and cooled in an ice bath. The mixture was treated with SOCl ₂ (3.5 eq) and stirred at 5° C. for 16 hours. HPLC at that time still showed about 10% mixture of mono and di-acetate intermediates, so additional SOCl ₂ (1 eq) was added and stirring was continued for 5 h. The product was precipitated by the addition of MTBE to give a white solid, which was triturated several times with MTBE. The crude product was redissolved in 10 mL anhydrous MeOH and precipitated with MTBE as previously described. The product was filtered and washed with 2 x 5 mL portions of ice-cold MeOH followed by copious amounts of MTBE. After drying under high vacuum for several hours, the product was obtained as a white solid (100 mg, 13%).
¹ H NMR (D ₂ O): δ 9.72 (s, 1H), 9.28 (d, 1H), 9.08 (d, 1H), 8.93 (apparent d, 1H), 8.44 (dd, 1H), 8.32 (t , 1H), 8.10 (apparent d, 4H), 6.25 (d, 1H), 4.53 (t, 1H), 4.46 (m, 1H), 4.34 (t, 1H), 3.95 (ab q, 2H), 3.92 (s, 3H).MS(ESI+) m/z = 390.1

[Example 32]
Compound 32

一般手順Bに従う:TMS-トリフレート(1.2当量)を、CH₃CN(15mL)中の対応するニコチンアミド化合物(1.6mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加する。周囲温度で2時間撹拌し、溶媒を除去してMeOH中のSOCl₂(3.5当量)で処理した後、溶液を5℃で16時間撹拌する。HPLCで10%のモノ-アセテートの残留が示された場合、追加のSOCl₂(0.1mL)を添加し、撹拌を6時間継続する。MTBEで研和した後、粗生成物を固体として得る。ISCO(12gのカートリッジ、DCM中5%MeOHからDCM中30%MeOHの勾配での溶出)での精製により、生成物を固体として得る。

According to general procedure B: TMS-triflate (1.2 eq) was added to the corresponding nicotinamide compound (1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose in _CH3CN (15 mL). (1.1 eq.) is added to the stirred mixture. After stirring at ambient temperature for 2 hours, removing the solvent and treating with SOCl ₂ (3.5 eq) in MeOH, the solution is stirred at 5° C. for 16 hours. When HPLC indicated 10% mono-acetate remaining, additional SOCl ₂ (0.1 mL) was added and stirring continued for 6 h. The crude product is obtained as a solid after trituration with MTBE. Purification by ISCO (12 g cartridge, elution with a gradient of 5% MeOH in DCM to 30% MeOH in DCM) gives the product as a solid.

[Example 33]
compound 33

一般手順Bに従う:TMS-トリフレート(1.2当量)を、CH₃CN(15mL)中の対応するニコチンアミド化合物(1.6mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加する。周囲温度で2時間撹拌し、溶媒を除去してMeOH中のSOCl₂(3.5当量)で処理した後、溶液を5℃で16時間撹拌する。HPLCで10%のモノ-アセテートの残留が示された場合、追加のSOCl₂(0.1mL)を添加し、撹拌を6時間継続する。MTBEで研和した後、粗生成物を固体として得る。ISCO(12gのカートリッジ、DCM中5%MeOHからDCM中30%MeOHの勾配での溶出)での精製により、生成物を固体として得る。

According to general procedure B: TMS-triflate (1.2 eq) was added to the corresponding nicotinamide compound (1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose in _CH3CN (15 mL). (1.1 eq.) is added to the stirred mixture. After stirring at ambient temperature for 2 hours, removing the solvent and treating with SOCl ₂ (3.5 eq) in MeOH, the solution is stirred at 5° C. for 16 hours. When HPLC indicated 10% mono-acetate remaining, additional SOCl ₂ (0.1 mL) was added and stirring continued for 6 h. The crude product is obtained as a solid after trituration with MTBE. Purification by ISCO (12 g cartridge, elution with a gradient of 5% MeOH in DCM to 30% MeOH in DCM) gives the product as a solid.

[Example 34]
compound 34

一般手順Bに従う:TMS-トリフレート(1.2当量)を、CH₃CN(15mL)中の対応するニコチンアミド化合物(1.6mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加する。周囲温度で2時間撹拌し、溶媒を除去してMeOH中のSOCl₂(3.5当量)で処理した後、溶液を5℃で16時間撹拌する。HPLCで10%のモノ-アセテートの残留が示された場合、追加のSOCl₂(0.1mL)を添加し、撹拌を6時間継続する。MTBEで研和した後、粗生成物を固体として得る。ISCO(12gのカートリッジ、DCM中5%MeOHからDCM中30%MeOHの勾配での溶出)での精製により、生成物を固体として得る。

According to general procedure B: TMS-triflate (1.2 eq) was added to the corresponding nicotinamide compound (1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose in _CH3CN (15 mL). (1.1 eq.) is added to the stirred mixture. After stirring at ambient temperature for 2 hours, removing the solvent and treating with SOCl ₂ (3.5 eq) in MeOH, the solution is stirred at 5° C. for 16 hours. When HPLC indicated 10% mono-acetate remaining, additional SOCl ₂ (0.1 mL) was added and stirring continued for 6 h. The crude product is obtained as a solid after trituration with MTBE. Purification by ISCO (12 g cartridge, elution with a gradient of 5% MeOH in DCM to 30% MeOH in DCM) gives the product as a solid.

[Example 35]
Compound 35

一般手順Bに従う:TMS-トリフレート(1.2当量)を、CH₃CN(15mL)中の対応するニコチンアミド化合物(1.6mmol)及び1,2,3,5-テトラアセチル-β-D-リボフラノース(1.1当量)の撹拌混合物に添加する。周囲温度で2時間撹拌し、溶媒を除去してMeOH中のSOCl₂(3.5当量)で処理した後、溶液を5℃で16時間撹拌する。HPLCで10%のモノ-アセテートの残留が示された場合、追加のSOCl₂(0.1mL)を添加し、撹拌を6時間継続する。MTBEで研和した後、粗生成物を固体として得る。ISCO(12gのカートリッジ、DCM中5%MeOHからDCM中30%MeOHの勾配での溶出)での精製により、生成物を固体として得る。

According to general procedure B: TMS-triflate (1.2 eq) was added to the corresponding nicotinamide compound (1.6 mmol) and 1,2,3,5-tetraacetyl-β-D-ribofuranose in _CH3CN (15 mL). (1.1 eq.) is added to the stirred mixture. After stirring at ambient temperature for 2 hours, removing the solvent and treating with SOCl ₂ (3.5 eq) in MeOH, the solution is stirred at 5° C. for 16 hours. When HPLC indicated 10% mono-acetate remaining, additional SOCl ₂ (0.1 mL) was added and stirring continued for 6 h. The crude product is obtained as a solid after trituration with MTBE. Purification by ISCO (12 g cartridge, elution with a gradient of 5% MeOH in DCM to 30% MeOH in DCM) gives the product as a solid.

[Example 36]
compound 36

乾燥100mLフラスコに、4.1mmolの化合物17を入れる。フラスコをアルゴンでフラッシュし、10mLのリン酸トリメチルを添加する。得られた溶液を0℃に冷却し、POCl₃(8.2mmol、2当量)で処理する。フラスコを密閉し、冷凍庫内で-10℃で静置する。2.5時間後、均質溶液をトリエチルアミン(2.0mmol)で数分間にわたり処理し、冷凍庫内で一晩静置する。反応混合物を氷浴中で冷却し、十分に撹拌した懸濁液を水(82mmol)で数分間にわたり、続いて固体NaHCO₃(28.7mmol)で処理し、撹拌を0℃で90分間継続する。反応混合物を、33mmolの90%ギ酸を含有する100mLのCH₃CNで処理し、固体を生成する。固体を濾過により回収し、CH₃CNで洗浄し、高真空下に置いて、粗生成物を得る。この材料を、50gのアミノプロピル官能化シリカを含有するカラムで、中圧クロマトグラフィーにより精製する。生成物を、100mMのギ酸を含有する25mLの60%/40% MeOH-CH₃CNに溶解し、カラムを同じ溶媒混合物で平衡化する。生成物含有画分を合わせて濃縮し、水(3×25mL)から共蒸発させ、冷凍及び凍結乾燥させて、生成物を得る。

A dry 100 mL flask is charged with 4.1 mmol of compound 17. Flush the flask with argon and add 10 mL of trimethyl phosphate. The resulting solution is cooled to 0° C. and treated with POCl ₃ (8.2 mmol, 2 eq). The flask is sealed and placed in a freezer at -10°C. After 2.5 hours, the homogenous solution is treated with triethylamine (2.0 mmol) for several minutes and left overnight in the freezer. The reaction mixture is cooled in an ice bath and the well-stirred suspension is treated with water (82 mmol) over several minutes followed by solid NaHCO ₃ (28.7 mmol) and stirring is continued at 0° C. for 90 minutes. The reaction mixture is treated with 100 mL of CH ₃ CN containing 33 mmol of 90% formic acid to produce a solid. The solids are collected by filtration, washed with _CH3CN and placed under high vacuum to give crude product. This material is purified by medium pressure chromatography on a column containing 50 g of aminopropyl-functionalized silica. The product is dissolved in 25 mL of 60%/40% MeOH- _CH3CN containing 100 mM formic acid and the column is equilibrated with the same solvent mixture. The product-containing fractions are combined, concentrated, co-evaporated from water (3 x 25 mL), frozen and lyophilized to give the product.

[Example 37]
compound 37

乾燥100mLフラスコに、4.1mmolの化合物13を入れる。フラスコをアルゴンでフラッシュし、10mLのリン酸トリメチルを添加する。得られた溶液を0℃に冷却し、POCl₃(8.2mmol、2当量)で処理する。フラスコを密閉し、冷凍庫内で-10℃で静置する。2.5時間後、均質溶液をトリエチルアミン(2.0mmol)で数分間にわたり処理し、冷凍庫内で一晩静置する。反応混合物を氷浴中で冷却し、十分に撹拌した懸濁液を水(82mmol)で数分間にわたり、続いて固体NaHCO₃(28.7mmol)で処理し、撹拌を0℃で90分間継続する。反応混合物を、33mmolの90%ギ酸を含有する100mLのCH₃CNで処理し、固体を生成する。固体を濾過により回収し、CH₃CNで洗浄し、高真空下に置いて、粗生成物を得る。この材料を、50gのアミノプロピル官能化シリカを含有するカラムで、中圧クロマトグラフィーにより精製する。生成物を、100mMのギ酸を含有する25mLの60%/40% MeOH-CH₃CNに溶解し、カラムを同じ溶媒混合物で平衡化する。生成物含有画分を合わせて濃縮し、水(3×25mL)から共蒸発させ、冷凍及び凍結乾燥させて、生成物を得る。

A dry 100 mL flask is charged with 4.1 mmol of compound 13. Flush the flask with argon and add 10 mL of trimethyl phosphate. The resulting solution is cooled to 0° C. and treated with POCl ₃ (8.2 mmol, 2 eq). The flask is sealed and placed in a freezer at -10°C. After 2.5 hours, the homogenous solution is treated with triethylamine (2.0 mmol) for several minutes and left overnight in the freezer. The reaction mixture is cooled in an ice bath and the well-stirred suspension is treated with water (82 mmol) over several minutes followed by solid NaHCO ₃ (28.7 mmol) and stirring is continued at 0° C. for 90 minutes. The reaction mixture is treated with 100 mL of CH ₃ CN containing 33 mmol of 90% formic acid to produce a solid. The solids are collected by filtration, washed with _CH3CN and placed under high vacuum to give crude product. This material is purified by medium pressure chromatography on a column containing 50 g of aminopropyl-functionalized silica. The product is dissolved in 25 mL of 60%/40% MeOH- _CH3CN containing 100 mM formic acid and the column is equilibrated with the same solvent mixture. The product-containing fractions are combined, concentrated, co-evaporated from water (3 x 25 mL), frozen and lyophilized to give the product.

biological assay
[Example B1]
General Assay—2×10 ³ Hek293 (human embryonic kidney) and HepG2 (human hepatocellular carcinoma) cells seeded per well in a 96-well clear-bottom black plate were O/N attached. The next day, cells were treated with 2 mM NMN or 500 μM other compounds, and after 24 hours of treatment, cells were analyzed with CellTiter-Fluor and NAD assays.

1A and 1B show NAD(H) in cells after treatment with control or compound according to Formula 1. FIG. Figure 1A is from Hek293 cells (human embryonic kidney cells), while Figure 1B is from HepG2 cells (human hepatocellular carcinoma cells). In both FIGS. 1A and 1B, the Y-axis is the amount of NAD(H)/number of viable cells, normalized to 1.0 to no treatment, and the X-axis is as follows:
1: (control) - no treatment
2: (control) - treatment with nicotinamide mononucleotide (NMN)
3: (control) - treatment with PABA-methyl
4: Treatment with Compound 1
5: (Control) - Treatment with Compound A
6: Treatment with Compound 9
7: Treatment with Compound 7
8: Treatment with Compound 8
9: Treatment with Compound 6
10: Treatment with Compound 2
11: Treatment with Compound 4
12: Treatment with Compound 3
13: Treatment with Compound 5

[Example B2]
Figures 2A, 2B and 2C show NAD(H) in normal cells after control or treatment with Compound 1 according to Formula 2a. Figure 2A is from AML12 (2K/well) cells (mouse normal hepatocytes), Figure 2B is from Hek293 cells (human embryonic kidney cells) and Figure 2C is from primary hPBMC cells (human peripheral blood cells). nuclear cells). In Figures 2A and 2B, the Y-axis is the amount of NAD(H)/number of viable cells normalized to 1.0 to no treatment. In FIG. 2C, the Y-axis shows pg of NAD(H)/micrograms of total protein normalized to 1.0 to no treatment.

In Figure 2A, the X-axis is as follows:
1: (control) - no treatment
2: (control) - treatment with nicotinamide mononucleotide (NMN), 2 mM
3: (control) - treatment with nicotinamide mononucleotide (NMN), 0.5 mM
4: (control) - treatment with ethanol
5: Treatment with compound 1, 0.5 mM
6: Treatment with compound 1, 0.25 mM

In Figure 2B, the X-axis is as follows:
1: (control) - no treatment
2: (control) - treatment with nicotinamide mononucleotide (NMN), 800 μM
3: (control) - no treatment (preparation 1)
4: Treatment with Compound 1, 800 μM (Preparation 1)
5: (control) - no treatment (preparation 2)
6: Treatment with Compound 1, 800 μM (Preparation 2)

In Figure 2C, the X-axis is as follows:
1: (control) - no treatment
2: (control) - treatment with nicotinamide mononucleotide (NMN), 1 mM
3: Treatment with Compound 1, 1 mM

[Example B3]
3A, 3B, 3C and 3D show NAD(H) in cancer cells after control or treatment with Compound 1 according to Formula 1. FIG. Figure 3A is from B16-F10 cells (mouse melanoma), Figure 3B is from RAW264.7 cells (mouse tumor-derived macrophages) and Figure 3C is from Jurkat cells (human acute T-cell leukemia). Figure 3D is from HepG2 cells (human hepatocellular carcinoma). In Figures 3B and 3D, the Y-axis is the amount of NAD(H)/number of viable cells, normalized to 1.0 to no treatment. In Figures 3A and 3C, the Y-axis is pg of NAD(H)/μg of total protein normalized to 1.0 to no treatment.

In Figure 3A, the X-axis is as follows:
1: (control) no treatment
2: (Control) NMN 1 mM
3: (Control) NMN 250 μM
4: Compound 1, 250 μM
5: Compound 1, 500 μM
6: (Control) PABA, 250 μM
7: (Control) PABA, 500 μM
8: (control) PABA methyl ester, 250 μM
9: (control) PABA methyl ester, 500 μM

In Figure 3B, the X-axis is as follows:
1: (control) no treatment
2: (control) NMN, 2 mM
3: (Control) NMN, 500 μM
4: Compound 1, 500 μM
5: Compound 1, 250 μM

In FIG. 3C, the X-axis is as follows:
1: (control) no treatment
2: (control) NMN, 2 mM
3: (control) NMN, 1 mM
4: (Control) NMN, 500 μM
5: (Control) NMN, 250 μM
6: Compound 1, 500 μM
7: Compound 1, 250 μM

In Figure 3D, the X-axis is as follows:
1: (control) no treatment
2: (control) NMN 800 μM
3: (Control) No treatment (Preparation 1)
4: Compound 1, 800 μM (Preparation 1)
5: (Control) No treatment (Preparation 2)
6: Compound 1, 800 μM (Preparation 2)

[Example B4]
Figures 4A and 4B show NAD(H) levels and viability in control or normal cells (Hek293 cells/human embryonic kidney cells) after treatment with compound 1 according to formula 1 as an indicator of cytotoxicity/cytostatics. indicates In FIG. 4A, the Y-axis shows the amount of NAD(H)/number of viable cells, normalized to 1.0 to no treatment, and the X-axis reflects the number of days of treatment. In FIG. 4B, the Y-axis shows cell number as a measure of viability, normalized to 1.0 to no treatment, and the X-axis reflects days.

[Example B5]
Figures 5A and 5B show NAD(H) levels and survival in cancer cells (HepG2 cells/human hepatocellular carcinoma) after control or treatment with Compound 1 according to Formula 1 as an index of cytotoxicity/cytostatics. Show ability. In FIG. 5A, the Y-axis shows the amount of NAD(H)/number of viable cells, normalized to 1.0 to no treatment, and the X-axis reflects the number of days of treatment. In FIG. 5B, the Y-axis shows cell number as a measure of viability, normalized to 1.0 to no treatment, and the X-axis reflects days.

4A, 4B, 5A and 5B the following legends apply:
i. (control) untreated
ii. (control) nicotinamide mononucleotide (NMN)
iii. Compound 1
iv. Compound 1+NMN
v.(Control) FK866
vi. (Control) FK866+NMN

[Example B6]
General Assay for Figures 6A and 6B: Hek293 (human embryonic kidney) and HepG2 (human hepatocellular carcinoma) cells seeded per well were O/N attached in 96-well clear-bottom black plates. The next day, cells were treated with 2 mM NMN or 250 μM other compounds and after 24 hours of treatment, cells were analyzed with CellTiter-Fluor and NAD assays.

FIG. 6A shows NAD(H) levels in normal cells (Hek293 cells/human embryonic kidney cells) after control or treatment with various compounds. In FIG. 6A, the Y-axis shows the amount of NAD(H)/number of viable cells, normalized to 1.0 to no treatment.

FIG. 6B shows NAD(H) levels in cancer cells (HepG2 cells/human hepatocellular carcinoma) after control or treatment with various compounds. In FIG. 6B, the Y-axis shows the amount of NAD(H)/number of viable cells, normalized to 1.0 to no treatment.

In both Figures 6A and 6B, the X-axis is as follows:
1: (control) - no treatment
2: (control) - treatment with nicotinamide mononucleotide (NMN)
3: (control) - treatment with PABA-nicotinamide (PABA nicotinate methyl ester)
4: (control) - treated with DMSO vehicle
5: Treatment with Compound 1
6: Treatment with Compound 12
7: Treatment with Compound 13
8: Treatment with Compound 14
9: Treatment with Compound 15
10: Treatment with Compound 16
11: Treatment with Compound 17
12: Treatment with Compound 18
13: Treatment with Compound 19
14: Treatment with Compound 20
15: Treatment with Compound 21
16: Treatment with Compound 22
17: Treatment with Compound 23
18: Treatment with Compound 24

Claims (41)

Equation 1:

and/or one or more salts thereof, wherein:
Ring A is carbocyclic or heterocyclic, said carbocyclic or heterocyclic ring being aromatic;
X is H or a phosphate group;
R ₁ is H, a C ₁ -C ₆ alkyl group, a substituted or unsubstituted carbocyclic ring which may be aromatic or non-aromatic when taken together with R ₂ and aromatic when taken together with R ₂ or a substituted or unsubstituted heterocyclic ring which may be non-aromatic;
Each R ₂ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or from unsubstituted C ₁ -C ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, and substituted or unsubstituted heterocyclic rings which when taken together with R ₁ may be aromatic or non-aromatic selected;
Each R ₃ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C ₁ -C ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, substituted or unsubstituted carboxamides, substituted or which together with R ₄ may be aromatic or non-aromatic selected from unsubstituted carbocycle and substituted or unsubstituted heterocycle which, when taken together with _R4 , may be aromatic or non-aromatic;
R ₄ is H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C _{1 -C6} alkoxy groups, carboxylic acids, substituted or unsubstituted C1 _{- C6} carboxyesters, substituted or unsubstituted carboxamides, cyano groups, substituted or unsubstituted sulfamoyl groups, substituted or unsubstituted carbons which may be aromatic or non-aromatic ring or heterocycle; substituted or unsubstituted carbocyclic ring _, which when taken together with R3 may be aromatic or non _- aromatic; and substituted or unsubstituted carbocyclic ring, which when taken together with R3 may be aromatic or A compound selected from substituted heterocycles. Equation 2:

and/or one or more salts thereof, wherein:
X is H or a phosphate group;
R ₁ is H or a C ₁ -C ₆ alkyl group;
Each R ₂ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl groups, substituted or unsubstituted C ₁ -C ₆ alkenyl groups, substituted or unsubstituted C ₁ -C ₆ alkynyl groups, and substituted or selected from unsubstituted C1 _{- C6} alkoxy groups;
Each R ₃ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C ₁ -C ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, substituted or unsubstituted carboxamides, substituted or which together with R ₄ may be aromatic or non-aromatic selected from unsubstituted carbocycle and substituted or unsubstituted heterocycle which, when taken together with _R4 , may be aromatic or non-aromatic;
R ₄ is H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C ₁ ~C6 alkoxy groups, carboxylic acids, substituted or unsubstituted C1 _{- C6} carboxyesters, substituted or unsubstituted carboxamides _, substituted or unsubstituted carbocycles which together with R3 may be aromatic or non _- aromatic , and a substituted or unsubstituted heterocyclic ring which, when taken together with R3 _, may be aromatic or non-aromatic. Equation 2a:

and/or one or more salts thereof, wherein
R ₃ is independently H, substituted or unsubstituted carbocyclic ring which when taken together with R ₄ may be aromatic or non-aromatic, and when taken together with R ₄ may be aromatic or non-aromatic selected from good substituted or unsubstituted heterocycles;
R ₄ is independently H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted substituted or unsubstituted C ₁ -C ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, substituted or unsubstituted carboxamides _, substituted or unsubstituted is selected from substituted carbocycle, and substituted or unsubstituted heterocycle which, when taken together with R3 _, may be aromatic or non-aromatic;
_3. The compound of Claim 2, further wherein at least one of R3 and _R4 is not H. 4. A compound according to claim 2 or 3, wherein R ₃ is H; and R ₄ is selected from carboxylic acids, substituted or unsubstituted C ₁ -C ₆ carboxyesters, and substituted or unsubstituted carboxamides. 5. A compound according to any one of claims 2 to 4, wherein X is H; and _R4 is a carboxymethyl ester group. 6. A compound according to any one of claims 2 to 5, selected from compounds 1 to 5, 11, 12, 14, 15, 18, 19, 21, 23, 24, 26, 27, 29, 32 and 35. Compound of:

. Equation 2b:

and/or one or more salts thereof, wherein
R ₁ is H or a C ₁ -C ₆ alkyl group;
R ₂ is selected from H and substituted or unsubstituted C ₁ -C ₆ alkoxy groups;
_R3 is H;
3. The compound of claim 2, further wherein at least one of _R1 and _R2 is not H. 8. The compound of claim 7, wherein _R1 is a methyl group. 8. The compound of Claim 7, wherein _R2 is a methoxy group. Compounds 6 and 7:

8. A compound according to claim 7, selected from Equation 2c:

and/or one or more salts thereof, wherein
R ₂ is selected from H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl groups, substituted or unsubstituted C ₁ -C ₆ alkenyl groups, and substituted or unsubstituted C ₁ -C ₆ alkynyl groups;
R ₃ is H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C _{1 -C6} alkoxy groups, carboxylic acids, substituted or unsubstituted C1 _{- C6} carboxyesters, and substituted or unsubstituted carboxamides;
R ₄ is H, substituted or unsubstituted C ₁ -C ₆ alkyl group, substituted or unsubstituted C ₁ -C ₆ alkenyl group, substituted or unsubstituted C ₁ -C ₆ alkynyl group, substituted or unsubstituted C ₁ -C 6 ₆ alkoxy groups, carboxylic acids, substituted or unsubstituted C1 _{- C6} carboxyesters, and substituted or unsubstituted carboxamides;
_3. The compound of Claim 2, further wherein at least one of _R2 and R3 is not H. 12. The compound of claim 11, wherein _R2 is halogen. 12. The compound of claim ₁₁ , wherein R ₃ is selected from carboxylic acids, substituted or unsubstituted C1 _- C6 carboxyesters, and substituted or unsubstituted carboxamides. Compounds 8, 9, 16, and 20:

12. A compound according to claim 11, selected from Compounds 10, 13, 17, 22, 25, 28, 30, 31, 33, 34, 36, and 37:

2. The compound of claim 1, selected from Said salt is formed with cations selected from H ⁺ , Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ and Ca ²⁺ and/or said salt is formed with acetate ion, trifluoromethanesulfonic acid (trifluoromethane) rate) ions, halide ions, trifluoroacetate ions, formate ions, _H2PO4- ^, _HPO42- , ^{OH- ,} _HSO4- ^{, SO42-} _{, NO3-} ^, _{HCO3- ,} ^and _CO3 16. A compound according to any one of claims 1 to 15 formed with an anion selected from ^2- . 16. The compound of any one of claims 1-15, which is a zwitterion. 18. A composition comprising a compound according to any one of claims 1-17 and a pharmaceutically acceptable excipient or carrier. The pharmaceutically acceptable excipients or carriers are anti-adherents, binders, coatings, dyes, disintegrants, flavoring agents, lubricants, lubricants, preservatives, sorbents, sweeteners, dispersants, diluents. 19. The composition of claim 18, selected from liquids, fillers, granulating agents, coating agents, waxes, suspending agents, wetting agents and vehicles, and combinations thereof. From tablets, pills, capsules, caplets, lozenges, granules, powders, sachets, inhalable powders, chewables, flavored tablets, lozenges, intravenous solutions, and liquid forms suitable for infusion or injection. 20. A composition according to claim 18 or 19 in a selected form. 21. The composition according to any one of claims 18-20, wherein said compound is present as an active pharmaceutical ingredient in a pharmaceutically effective amount. 22. The composition of any one of claims 18-21, further comprising a pharmaceutically effective amount of an additional active pharmaceutical ingredient. Differentially modulating nicotinamide adenine dinucleotide (NAD) levels in two or more tissues or cell types comprising administering a compound or composition according to any one of claims 1-22 The method, wherein said administering induces a differential response of NAD levels in a first tissue or cell type and a second tissue or cell type. wherein said differential response in NAD levels is at least 10% difference in NAD levels, at least 20% difference in NAD levels, at least 30% difference in NAD levels, at least 40% difference in NAD levels, and 24. The method of claim 23, selected from a difference of at least 50%. wherein said differential response in NAD levels is at least a 10% increase in NAD levels in said first tissue or cell type compared to untreated NAD levels and said second tissue or cell compared to untreated NAD levels 24. The method of claim 23, wherein there is at least a 10% concomitant decrease in NAD levels in mold. said differential response of NAD levels is maintained within 10% of NAD levels in said first tissue or cell type compared to untreated NAD levels, and said second tissue or cell compared to untreated NAD levels 24. The method of claim 23, wherein there is at least a 10% concomitant decrease in NAD levels in mold. wherein said differential response in NAD levels is at least a 10% reduction in NAD levels in said first tissue or cell type compared to untreated NAD levels and said second tissue or cell compared to untreated NAD levels a concomitant reduction in NAD levels in the second tissue or cell type, wherein said reduction in said second tissue or cell type is at least 10 percentage points, at least 20 percentage points, at least 30 percent greater than said reduction in said first tissue or cell type 24. The method of claim 23, selected from a reduction in points, at least 40 percentage points, or at least 50 percentage points greater. 28. The method of any one of claims 23-27, wherein said first tissue or cell type is normal tissue or cells and said second tissue or cell type is neoplastic or cancerous. . 29. The method of any one of claims 23-28, which is the treatment of cancer in an individual in need thereof. wherein said method exhibits a selective cytostatic or cytotoxic effect, said effect decreasing viability of neoplastic or cancerous tissue or cells compared to untreated neoplastic or cancerous tissue or cells. 30. A method according to any one of claims 23 to 29, indicated by in an individual wherein said first tissue or cell type is a normal tissue or cell and said method is in need of treatment to promote health or increase biological activity of said first tissue or cell type 27. The method of any one of claims 23-26, which is a treatment for promoting health or increasing biological activity of said first tissue or cell type. 32. The method of claim 31, wherein said treatment does not induce an increased risk of cancer diagnosis in said individual. 32. The method of claim 31, wherein said treatment reduces the risk of cancer diagnosis in said individual. 23. A method of treating or suppressing cancer in an individual in need thereof comprising administering a compound or composition according to any one of claims 1-22. 1. A method of increasing or maintaining healthy tissue or cells in an individual in need thereof without increasing the risk of growing neoplastic or cancerous tissue or cells comprising: 23. A method comprising administering a compound or composition according to any one of claims 1-22. 1. A method of increasing or maintaining healthy tissue or cells in an individual in need thereof while inhibiting the growth of neoplastic or cancerous tissue or cells, comprising: 23. A method comprising administering a compound or composition according to any one of 22. 23. A method of increasing or maintaining nicotinamide adenine dinucleotide (NAD) levels in at least one healthy tissue or cell type, comprising administering a compound or composition according to any one of claims 1-22 to said A method comprising administering to a healthy tissue or cell type. 23. A method of reducing the viability of at least one cancerous tissue or cell type, comprising administering a compound or composition according to any one of claims 1 to 22 to said cancerous tissue or cell type. a method comprising: 23. A method of modulating the level of NAD in at least one tissue or cell type in a mixture of tissues or cell types, comprising: methods comprising targeted delivery to two tissues or cell types. 40. The method of claim 39, wherein said targeted delivery is non-systemic. 18. A method of synthesizing a compound according to any one of claims 1 to 17, comprising reacting an amine-containing precursor with a nicotinic acid riboside precursor under conditions conducive to condensation of said precursor, 18. A method comprising producing a compound according to any one of 17.

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